MicroRNA-Based Methods and Compositions For the Diagnosis, Prognosis and Treatment of Breast Cancer

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application claiming the benefit of U.S. application Ser. No. 12/012,235, now U.S. Pat. No. ______, issued ______, 2014, which entered the National Phase on Jan. 31, 2008, from the International PCT Application No. US06/029889, filed Jul. 31, 2006, which claims the benefit of U.S. Provisional Application No. 60/704,464, filed Aug. 1, 2005. The disclosures of each of the aforementioned applications are incorporated herein by reference for all purposes.

GOVERNMENT SUPPORT

This invention was supported by a grant under Program Project Grant P01CA76259, P01CA81534, and P30CA56036 from the National Cancer Institute. The Government has certain rights in this invention.

BACKGROUND OF THE INVENTION

Breast cancer is a significant health problem for women in the United States and throughout the world. Although advances have been made in the detection and treatment of the disease, breast cancer remains the second leading cause of cancer-related deaths in women, affecting more than 180,000 women in the United States each year. For women in North America, the life-time odds of getting breast cancer are now one in eight.

No universally successful method for the treatment or prevention of breast cancer is currently available. Management of breast cancer currently relies on a combination of early diagnosis (for example, through routine breast screening procedures) and aggressive treatment, which may include one or more of a variety of treatments, such as surgery, radiotherapy, chemotherapy and hormone therapy. The course of treatment for a particular breast cancer is often selected based on a variety of prognostic parameters including an analysis of specific tumor markers.

Although the discovery of BRCA1 and BRCA2 were important steps in identifying key genetic factors involved in breast cancer, it has become clear that mutations in BRCA1 and BRCA2 account for only a fraction of inherited susceptibility to breast cancer. In spite of considerable research into therapies for breast cancer, breast cancer remains difficult to diagnose and treat effectively, and the high mortality observed in breast cancer patients indicates that improvements are needed in the diagnosis, treatment and prevention of the disease.

MicroRNAs are a class of small, non-coding RNAs that control gene expression by hybridizing to and triggering either translational repression or, less frequently, degradation of a messenger RNA (mRNA) target. The discovery and study of miRNAs has revealed miRNA-mediated gene regulatory mechanisms that play important roles in organismal development and various cellular processes, such as cell differentiation, cell growth and cell death. Recent studies suggest that aberrant expression of particular miRNAs may be involved in human diseases, such as neurological disorders and cancer. In particular, misexpression of miR-16-1 and/or miR-15a has been found in human chronic lymphocytic leukemias.

The development and use of microarrays containing all known human microRNAs has permitted a simultaneous analysis of the expression of every miRNA in a sample. These microRNA microarrays have not only been used to confirm that miR-16-1 is deregulated in human CLL cells, but also to generate miRNA expression signatures that are associated with well-defined clinico-pathological features of human CLL.

The use of microRNA microarrays to identify a group of microRNAs, which are differentially-expressed between normal cells and breast cancer cells (for example, an expression signature or expression profile), may help pinpoint specific miRNAs that are involved in breast cancer. Furthermore, the identification of putative targets of these miRNAs may help to unravel their pathogenic role. The present invention provides novel methods and compositions for the diagnosis, prognosis and treatment of breast cancer.

SUMMARY OF THE INVENTION

The present invention is based, in part, on the identification of a breast cancer-specific signature of miRNAs that are differentially-expressed in breast cancer cells, relative to normal control cells.

Accordingly, embodiments of the invention encompass methods of diagnosing whether a subject has, or is at risk for developing, breast cancer, comprising measuring the level of at least one miR gene product in a test sample from the subject and comparing the level of the miR gene product in the test sample to the level of a corresponding miR gene product in a control sample. An alteration (for example, an increase, a decrease) in the level of the miR gene product in the test sample, relative to the level of a corresponding miR gene product in a control sample, is indicative of the subject either having, or being at risk for developing, breast cancer. In certain embodiments, the at least one miR gene product is selected from the group consisting of miR-125b-1, miR125b-2, miR-145, miR-21, miR-155, miR-10b and combinations thereof.

The level of the at least one miR gene product can be measured using a variety of techniques that are well known to those of skill in the art. In one embodiment, the level of the at least one miR gene product is measured using Northern blot analysis. In another embodiment, the level of the at least one miR gene product is measured by reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligodeoxynucleotides, hybridizing the target oligodeoxynucleotides to a microarray that comprises miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample. An alteration in the signal of at least one miRNA in the test sample relative to the control sample is indicative of the subject either having, or being at risk for developing, breast cancer. In a particular embodiment, the microarray comprises miRNA-specific probe oligonucleotides for a substantial portion of the human miRNome. In a further embodiment, the microarray comprises miRNA-specific probe oligonucleotides for one or more miRNAs selected from the group consisting of miR-145, miR-21, miR-155, miR-10b, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, miR-213, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, let-7i (let-7d-v2), miR-101-1, miR-122a, miR-128b, miR-136, miR-143, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-205, miR-206, miR-210 and combinations thereof.

Embodiments of the invention also provide methods of diagnosing a breast cancer associated with one or more prognostic markers, comprising measuring the level of at least one miR gene product in a breast cancer test sample from a subject and comparing the level of the at least one miR gene product in the breast cancer test sample to the level of a corresponding miR gene product in a control sample. The breast cancer can be associated with one or more adverse prognostic markers associated with breast cancer, such as, but not limited to, estrogen receptor expression, progesterone receptor expression, positive lymph node metastasis, high proliferative index, detectable p53 expression, advanced tumor stage, and high vascular invasion. In one embodiment, the level of the at least one miR gene product is measured by reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligodeoxynucleotides, hybridizing the target oligodeoxynucleotides to a microarray that comprises miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample. An alteration in the signal of at least one miRNA in the test sample relative to the control sample is indicative of the subject either having, or being at risk for developing, a breast cancer associated with the one or more prognostic markers. In a particular embodiment, the microarray comprises at least one miRNA-specific probe oligonucleotide for a miRNA selected from the group consisting of miR-26a, miR-26b, miR-102 (miR-29b), miR-30a-5p, miR-30b, miR-30c, miR-30d, miR-185, miR-191, miR-206, miR-212, let-7c, miR-9-2, miR-15-a, miR-21, miR-30a-s, miR-133a-1, miR-137, miR-153-2, miR-154, miR-181a, miR-203, miR-213, let-7f-1, let-7a-3, let-7a-2, miR-9-3, miR-10b, miR-27a, miR-29a, miR-123, miR-205, let-7d, miR-145, miR-16a, miR-128b and combinations thereof.

Embodiments of the invention also encompass methods of treating breast cancer in a subject, wherein at least one miR gene product is de-regulated (for example, down-regulated, up-regulated) in the cancer cells of the subject. When the at least one isolated miR gene product is down-regulated in the breast cancer cells, the method comprises administering an effective amount of the at least one isolated miR gene product, such that proliferation of cancer cells in the subject is inhibited. In one embodiment, the method comprises administering an effective amount of the at least one isolated miR gene product, provided that the miR gene is not miR-15a or miR-16-1, such that proliferation of cancer cells in the subject is inhibited. When the at least one isolated miR gene product is up-regulated in the cancer cells, the method comprises administering to the subject an effective amount of at least one compound for inhibiting expression of the at least one miR gene, such that proliferation of breast cancer cells is inhibited.

In related embodiments, the invention provides methods of treating breast cancer in a subject, comprising determining the amount of at least one miR gene product in breast cancer cells from the subject, relative to control cells. If expression of the miR gene product is deregulated in breast cancer cells, the methods further comprise altering the amount of the at least one miR gene product expressed in the breast cancer cells. If the amount of the miR gene product expressed in the cancer cells is less than the amount of the miR gene product expressed in control cells, the method comprises administering an effective amount of at least one isolated miR gene product. In one embodiment, the miR gene product is not miR-15a or miR-16-1. If the amount of the miR gene product expressed in the cancer cells is greater than the amount of the miR gene product expressed in control cells, the method comprises administering to the subject an effective amount of at least one compound for inhibiting expression of the at least one miR gene. In one embodiment, the miR gene product is not miR-15a or miR-16-1.

The invention further provides pharmaceutical compositions for treating breast cancer. In one embodiment, the pharmaceutical compositions comprise at least one isolated miR gene product and a pharmaceutically-acceptable carrier. In a particular embodiment, the at least one miR gene product corresponds to a miR gene product that has a decreased level of expression in breast cancer cells relative to suitable control cells. In certain embodiments the isolated miR gene product is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In another embodiment, the pharmaceutical compositions of the invention comprise at least one miR expression inhibition compound. In a particular embodiment, the at least one miR expression inhibition compound is specific for a miR gene whose expression is greater in breast cancer cells than control cells. In certain embodiments, the miR expression inhibition compound is specific for one or more miR gene products selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

Embodiments of the invention also encompass methods of identifying an anti-breast cancer agent, comprising providing a test agent to a cell and measuring the level of at least one miR gene product in the cell. In one embodiment, the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with decreased expression levels in breast cancer cells. An increase in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, the at least one miR gene product associated with decreased expression levels in breast cancer cells is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In other embodiments the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with increased expression levels in breast cancer cells. A decrease in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, at least one miR gene product associated with increased expression levels in breast cancer cells is selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

FIG. 1 depicts a tree generated by cluster analysis showing a separation of breast cancer from normal tissues on the basis of differential microRNA expression (P<0.05). The bar at the bottom of the figure indicates the group of cancer (red) or normal breast tissues (yellow).

FIG. 2 is a graph depicting the probability (0.0 to 1.0) of each sample being a cancerous or normal tissue based on PAM analysis. All breast cancer and normal tissues were correctly predicted by the miR signature shown in Table 2.

FIG. 3A is a Northern blot depicting the expression level of miR-125b, using a miR-125b complementary probe, in a normal sample, as well as several tumor samples from breast cancer patients (P). The U6 probe was used for normalization of expression levels for each sample.

FIG. 3B is a Northern blot depicting the expression level of miR-145, using a miR-145 complementary probe, in a normal sample, as well as several tumor samples from breast cancer patients (P). The U6 probe was used for normalization of expression levels for each sample.

FIG. 3C is a Northern blot depicting the expression level of miR-21, using a miR-21 complementary probe, in a normal sample, as well as several tumor samples from breast cancer patients (labeled as numbered patients). The U6 probe was used for normalization of expression levels for each sample.

FIG. 3D is a Northern blot depicting the expression levels of microRNAs miR-125b, miR-145 and miR-21 in various breast cancer cell lines. The expression level of each microRNA was also determined in a sample from normal tissues. The U6 probe was used for normalization of expression levels for each sample.

FIG. 4A is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence (ER+) or absence (ER−) of estrogen receptor.

FIG. 4B is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence (PR+) or absence (PR−) of progesterone receptor.

FIG. 4C is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with stage 1 (pT1) or stage 2 or 3 (pT2-3) tumors.

FIG. 4D is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence (pN0) or absence (pN10+) of lymph node metastasis.

FIG. 4E is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with the presence or absence of vascular invasion.

FIG. 4F is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with a high (MIB-1>30) or low (MIB-1<20) proliferative index (PI).

FIG. 4G is a table listing miRNAs that are differentially-expressed in breast cancer samples associated with positive (p53+) or negative (p53−) immunostaining of p53.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the identification of particular miRNAs whose expression is altered in breast cancer cells relative to normal control cells, and microRNAs whose expression is altered in breast cancer cells associated with particular prognostic features, relative to breast cancer cells lacking such features.

As used herein interchangeably, a “miR gene product,” “microRNA,” “miR,” or “miRNA” refers to the unprocessed or processed RNA transcript from an miR gene. As the miR gene products are not translated into protein, the term “miR gene products” does not include proteins. The unprocessed miR gene transcript is also called an “miR precursor,” and typically comprises an RNA transcript of about 70-100 nucleotides in length. The miR precursor can be processed by digestion with an RNAse (for example, Dicer, Argonaut, or RNAse III, for example, E. coli RNAse III)) into an active 19-25 nucleotide RNA molecule. This active 19-25 nucleotide RNA molecule is also called the “processed” miR gene transcript or “mature” miRNA.

The active 19-25 nucleotide RNA molecule can be obtained from the miR precursor through natural processing routes (for example, using intact cells or cell lysates) or by synthetic processing routes (for example, using isolated processing enzymes, such as isolated Dicer, Argonaut, or RNAase III). It is understood that the active 19-25 nucleotide RNA molecule can also be produced directly by biological or chemical synthesis, without having been processed from the miR precursor.

The sequences of 187 miR gene products are provided in Table 1. All nucleic acid sequences herein are given in the 5′ to 3′ direction. In addition, genes are represented by italics, and gene products are represented by normal type; for example, mir-17 is the gene and miR-17 is the gene product.

The present invention encompasses methods of diagnosing whether a subject has, or is at risk for developing, breast cancer, comprising measuring the level of at least one miR gene product in a test sample from the subject and comparing the level of the miR gene product in the test sample to the level of a corresponding miR gene product in a control sample. As used herein, a “subject” can be any mammal that has, or is suspected of having, breast cancer. In a particular embodiment, the subject is a human who has, or is suspected of having, breast cancer.

The breast cancer can be any form of breast cancer and may be associated with one or more prognostic markers or features, including, but not limited to, estrogen receptor expression, progesterone receptor expression, lymph node metastasis, high proliferative index, detectable p53 expression, advanced tumor stage, and high vascular invasion. The prognostic marker can be associated with an adverse or negative prognosis, or it may be associated with a good or positive prognosis.

TABLE 1
Human miR Gene Product Sequences

		SEQ ID
Name	Precursor Sequence (5′ to 3′)*	NO.

hsa-let-7a-1-prec	CACTGTGGGATGAGGTAGTAGGTTGTATAGTTTTAGGGTCACACCCACCACT	1
	GGGAGATAACTATACAATCTACTGTCTTTCCTAACGTG
hsa-let-7a-2-prec	AGGTTGAGGTAGTAGGTTGTATAGTTTAGAATTACATCAAGGGAGATAACTG	2
	TACAGCCTCCTAGCTTTCCT
hsa-let-7a-3-prec	GGGTGAGGTAGTAGGTTGTATAGTTTGGGGCTCTGCCCTGCTATGGGATAAC	3
	TATACAATCTACTGTCTTTCCT
hsa-let-7a-4-prec	GTGACTGCATGCTCCCAGGTTGAGGTAGTAGGTTGTATAGTTTAGAATTACA	4
	CAAGGGAGATAACTGTACAGCCTCCTAGCTTTCCTTGGGTCTTGCACTAAAC
	AAC
hsa-let-7b-prec	GGCGGGGTGAGGTAGTAGGTTGTGTGGTTTCAGGGCAGTGATGTTGCCCCTC	5
	GGAAGATAACTATACAACCTACTGCCTTCCCTG
hsa-let-7c-prec	GCATCCGGGTTGAGGTAGTAGGTTGTATGGTTTAGAGTTACACCCTGGGAGT	6
	TAACTGTACAACCTTCTAGCTTTCCTTGGAGC
hsa-let-7d-prec	CCTAGGAAGAGGTAGTAGGTTGCATAGTTTTAGGGCAGGGATTTTGCCCACA	7
	AGGAGGTAACTATACGACCTGCTGCCTTTCTTAGG
hsa-let-7d-v1-	CTAGGAAGAGGTAGTAGTTTGCATAGTTTTAGGGCAAAGATTTTGCCCACAA	8
prec	GTAGTTAGCTATACGACCTGCAGCCTTTTGTAG
hsa-let-7d-v2-	CTGGCTGAGGTAGTAGTTTGTGCTGTTGGTCGGGTTGTGACATTGCCCGCTGT	9
prec	GGAGATAACTGCGCAAGCTACTGCCTTGCTAG
hsa-let-7e-prec	CCCGGGCTGAGGTAGGAGGTTGTATAGTTGAGGAGGACACCCAAGGAGATC	10
	ACTATACGGCCTCCTAGCTTTCCCCAGG
hsa-let-7f-1-prec	TCAGAGTGAGGTAGTAGATTGTATAGTTGTGGGGTAGTGATTTTACCCTGTT	11
	CAGGAGATAACTATACAATCTATTGCCTTCCCTGA
hsa-let-7f-2-prec	CTGTGGGATGAGGTAGTAGATTGTATAGTTGTGGGGTAGTGATTTTACCCTG	12
	TTCAGGAGATAACTATACAATCTATTGCCTTCCCTGA
hsa-let-7f-2-prec	CTGTGGGATGAGGTAGTAGATTGTATAGTTTTAGGGTCATACCCCATCTTGG	13
	AGATAACTATACAGTCTACTGTCTTTCCCACGG
hsa-let-7g-prec	TTGCCTGATTCCAGGCTGAGGTAGTAGTTTGTACAGTTTGAGGGTCTATGAT	14
	ACCACCCGGTACAGGAGATAACTGTACAGGCCACTGCCTTGCCAGGAACAG
	CGCGC
hsa-let-7i-prec	CTGGCTGAGGTAGTAGTTTGTGCTGTTGGTCGGGTTGTGACATTGCCCGCTGT	15
	GGAGATAACTGCGCAAGCTACTGCCTTGCTAG
hsa-mir-001b-1-	ACCTACTCAGAGTACATACTTCTTTATGTACCCATATGAACATACAATGCTAT	16
prec	GGAATGTAAAGAAGTATGTATTTTTGGTAGGC
hsa-mir-001b-1-	CAGCTAACAACTTAGTAATACCTACTCAGAGTACATACTTCTTTATGTACCCA	17
prec	TATGAACATACAATGCTATGGAATGTAAAGAAGTATGTATTTTTGGTAGGCA
	ATA
hsa-mir-001b-2-	GCCTGCTTGGGAAACATACTTCTTTATATGCCCATATGGACCTGCTAAGCTAT	18
prec	GGAATGTAAAGAAGTATGTATCTCAGGCCGGG
hsa-mir-001b-	TGGGAAACATACTTCTTTATATGCCCATATGGACCTGCTAAGCTATGGAATG	19
prec	TAAAGAAGTATGTATCTCA
hsa-mir-001d-	ACCTACTCAGAGTACATACTTCTTTATGTACCCATATGAACATACAATGCTAT	20
prec	GGAATGTAAAGAAGTATGTATTTTTGGTAGGC
hsa-mir-007-1	TGGATGTTGGCCTAGTTCTGTGTGGAAGACTAGTGATTTTGTTGTTTTTAGAT	21
	AACTAAATCGACAACAAATCACAGTCTGCCATATGGCACAGGCCATGCCTCT
	ACA
hsa-mir-007-1-	TTGGATGTTGGCCTAGTTCTGTGTGGAAGACTAGTGATTTTGTTGTTTTTAGA	22
prec	TAACTAAATCGACAACAAATCACAGTCTGCCATATGGCACAGGCCATGCCTC
	TACAG
hsa-mir-007-2	CTGGATACAGAGTGGACCGGCTGGCCCCATCTGGAAGACTAGTGATTTTGTT	23
	GTTGTCTTACTGCGCTCAACAACAAATCCCAGTCTACCTAATGGTGCCAGCC
	ATCGCA
hsa-mir-007-2-	CTGGATACAGAGTGGACCGGCTGGCCCCATCTGGAAGACTAGTGATTTTGTT	24
prec	GTTGTCTTACTGCGCTCAACAACAAATCCCAGTCTACCTAATGGTGCCAGCC
	ATCGCA
hsa-mir-007-3	AGATTAGAGTGGCTGTGGTCTAGTGCTGTGTGGAAGACTAGTGATTTTGTTG	25
	TTCTGATGTACTACGACAACAAGTCACAGCCGGCCTCATAGCGCAGACTCCC
	TTCGAC
hsa-mir-007-3-	AGATTAGAGTGGCTGTGGTCTAGTGCTGTGTGGAAGACTAGTGATTTTGTTG	26
prec	TTCTGATGTACTACGACAACAAGTCACAGCCGGCCTCATAGCGCAGACTCCC
	TTCGAC
hsa-mir-009-1	CGGGGTTGGTTGTTATCTTTGGTTATCTAGCTGTATGAGTGGTGTGGAGTCTT	27
	CATAAAGCTAGATAACCGAAAGTAAAAATAACCCCA
hsa-mir-009-2	GGAAGCGAGTTGTTATCTTTGGTTATCTAGCTGTATGAGTGTATTGGTCTTCA	28
	TAAAGCTAGATAACCGAAAGTAAAAACTCCTTCA
hsa-mir-009-3	GGAGGCCCGTTTCTCTCTTTGGTTATCTAGCTGTATGAGTGCCACAGAGCCGT	29
	CATAAAGCTAGATAACCGAAAGTAGAAATGATTCTCA
hsa-mir-010a-	GATCTGTCTGTCTTCTGTATATACCCTGTAGATCCGAATTTGTGTAAGGAATT	30
prec	TTGTGGTCACAAATTCGTATCTAGGGGAATATGTAGTTGACATAAACACTCC
	GCTCT
hsa-mir-010b-	CCAGAGGTTGTAACGTTGTCTATATATACCCTGTAGAACCGAATTTGTGTGG	31
prec	TATCCGTATAGTCACAGATTCGATTCTAGGGGAATATATGGTCGATGCAAAA
	ACTTCA
hsa-mir-015a-2-	GCGCGAATGTGTGTTTAAAAAAAATAAAACCTTGGAGTAAAGTAGCAGCAC	32
prec	ATAATGGTTTGTGGATTTTGAAAAGGTGCAGGCCATATTGTGCTGCCTCAAA
	AATAC
hsa-mir-015a-	CCTTGGAGTAAAGTAGCAGCACATAATGGTTTGTGGATTTTGAAAAGGTGCA	33
prec	GGCCATATTGTGCTGCCTCAAAAATACAAGG
hsa-mir-015b-	CTGTAGCAGCACATCATGGTTTACATGCTACAGTCAAGATGCGAATCATTAT	34
prec	TTGCTGCTCTAG
hsa-mir-015b-	TTGAGGCCTTAAAGTACTGTAGCAGCACATCATGGTTTACATGCTACAGTCA	35
prec	AGATGCGAATCATTATTTGCTGCTCTAGAAATTTAAGGAAATTCAT
hsa-mir-016a-	GTCAGCAGTGCCTTAGCAGCACGTAAATATTGGCGTTAAGATTCTAAAATTA	36
chr13	TCTCCAGTATTAACTGTGCTGCTGAAGTAAGGTTGAC
hsa-mir-016b-	GTTCCACTCTAGCAGCACGTAAATATTGGCGTAGTGAAATATATATTAAACA	37
chr3	CCAATATTACTGTGCTGCTTTAGTGTGAC
hsa-mir-016-	GCAGTGCCTTAGCAGCACGTAAATATTGGCGTTAAGATTCTAAAATTATCTC	38
prec-13	CAGTATTAACTGTGCTGCTGAAGTAAGGT
hsa-mit-017-prec	GTCAGAATAATGTCAAAGTGCTTACAGTGCAGGTAGTGATATGTGCATCTAC	39
	TGCAGTGAAGGCACTTGTAGCATTATGGTGAC
hsa-mir-018-prec	TGTTCTAAGGTGCATCTAGTGCAGATAGTGAAGTAGATTAGCATCTACTGCC	40
	CTAAGTGCTCCTTCTGGCA
hsa-mir-018-	TTTTTGTTCTAAGGTGCATCTAGTGCAGATAGTGAAGTAGATTAGCATCTACT	41
prec-13	GCCCTAAGTGCTCCTTCTGGCATAAGAA
hsa-mir-019a-	GCAGTCCTCTGTTAGTTTTGCATAGTTGCACTACAAGAAGAATGTAGTTGTG	42
prec	CAAATCTATGCAAAACTGATGGTGGCCTGC
hsa-mir-019a-	CAGTCCTCTGTTAGTTTTGCATAGTTGCACTACAAGAAGAATGTAGTTGTGC	43
prec-13	AAATCTATGCAAAACTGATGGTGGCCTG
hsa-mir-019b-1-	CACTGTTCTATGGTTAGTTTTGCAGGTTTGCATCCAGCTGTGTGATATTCTGC	44
prec	TGTGCAAATCCATGCAAAACTGACTGTGGTAGTG
hsa-mir-019b-2-	ACATTGCTACTTACAATTAGTTTTGCAGGTTTGCATTTCAGCGTATATATGTA	45
prec	TATGTGGCTGTGCAAATCCATGCAAAACTGATTGTGATAATGT
hsa-mir-019b-	TTCTATGGTTAGTTTTGCAGGTTTGCATCCAGCTGTGTGATATTCTGCTGTGC	46
prec-13	AAATCCATGCAAAACTGACTGTGGTAG
hsa-mir-019b-	TTACAATTAGTTTTGCAGGTTTGCATTTCAGCGTATATATGTATATGTGGCTG	47
prec--X	TGCAAATCCATGCAAAACTGATTGTGAT
hsa-mir-020-prec	GTAGCACTAAAGTGCTTATAGTGCAGGTAGTGTTTAGTTATCTACTGCATTAT	48
	GAGCACTTAAAGTACTGC
hsa-mir-021-prec	TGTCGGGTAGCTTATCAGACTGATGTTGACTGTTGAATCTCATGGCAACACC	49
	AGTCGATGGGCTGTCTGACA
hsa-mir-021-	ACCTTGTCGGGTAGCTTATCAGACTGATGTTGACTGTTGAATCTCATGGCAA	50
prec-17	CACCAGTCGATGGGCTGTCTGACATTTTG
hsa-mir-022-prec	GGCTGAGCCGCAGTAGTTCTTCAGTGGCAAGCTTTATGTCCTGACCCAGCTA	51
	AAGCTGCCAGTTGAAGAACTGTTGCCCTCTGCC
hsa-mir-023a-	GGCCGGCTGGGGTTCCTGGGGATGGGATTTGCTTCCTGTCACAAATCACATT	52
prec	GCCAGGGATTTCCAACCGACC
hsa-mir-023b-	CTCAGGTGCTCTGGCTGCTTGGGTTCCTGGCATGCTGATTTGTGACTTAAGAT	53
prec	TAAAATCACATTGCCAGGGATTACCACGCAACCACGACCTTGGC
hsa-mir-023-	CCACGGCCGGCTGGGGTTCCTGGGGATGGGATTTGCTTCCTGTCACAAATCA	54
prec-19	CATTGCCAGGGATTTCCAACCGACCCTGA
hsa-mir-024-1-	CTCCGGTGCCTACTGAGCTGATATCAGTTCTCATTTTACACACTGGCTCAGTT	55
prec	CAGCAGGAACAGGAG
hsa-mir-024-2-	CTCTGCCTCCCGTGCCTACTGAGCTGAAACACAGTTGGTTTGTGTACACTGGC	56
prec	TCAGTTCAGCAGGAACAGGG
hsa-mir-024-	CCCTGGGCTCTGCCTCCCGTGCCTACTGAGCTGAAACACAGTTGGTTTGTGTA	57
prec-19	CACTGGCTCAGTTCAGCAGGAACAGGGG
hsa-mir-024-	CCCTCCGGTGCCTACTGAGCTGATATCAGTTCTCATTTTACACACTGGCTCAG	58
prec-9	TTCAGCAGGAACAGCATC
hsa-mir-025-prec	GGCCAGTGTTGAGAGGCGGAGACTTGGGCAATTGCTGGACGCTGCCCTGGG	59
	CATTGCACTTGTCTCGGTCTGACAGTGCCGGCC
hsa-mir-026a-	AGGCCGTGGCCTCGTTCAAGTAATCCAGGATAGGCTGTGCAGGTCCCAATGG	60
prec	CCTATCTTGGTTACTTGCACGGGGACGCGGGCCT
hsa-mir-026b-	CCGGGACCCAGTTCAAGTAATTCAGGATAGGTTGTGTGCTGTCCAGCCTGTT	61
prec	CTCCATTACTTGGCTCGGGGACCGG
hsa-mir-027a-	CTGAGGAGCAGGGCTTAGCTGCTTGTGAGCAGGGTCCACACCAASGTCGTGTT	62
prec	CACAGTGGCTAAGTTCCGCCCCCCAG
hsa-mir-027b-	AGGTGCAGAGCTTAGCTGATTGGTGAACAGTGATTGGTTTCCGCTTTGTTCA	63
prec	CAGTGGCTAAGTTCTGCACCT
hsa-mir-027b-	ACCTCTCTAACAAGGTGCAGAGCTTAGCTGATTGGTGAACAGTGATTGGTTT	64
prec	CCGCTTTGTTCACAGTGGCTAAGTTCTGCACCTGAAGAGAAGGTG
hsa-mir-027-	CCTGAGGAGCAGGGCTTAGCTGCTTGTGAGCAGGGTCCACACCAAGTCGTGT	65
prec-19	TCACAGTGGCTAAGTTCCGCCCCCCAGG
hsa-mir-028-prec	GGTCCTTGCCCTCAAGGAGCTCACAGTCTATTGAGTTACCTTTCTGACTTTCC	66
	CACTAGATTGTGAGCTCCTGGAGGGCAGGCACT
hsa-mir-029a-2	CCTTCTGTGACCCCTTAGAGGATGACTGATTTCTTTTGGTGTTCAGAGTCAAT	67
	ATAATTTTCTAGCACCATCTGAAATCGGTTATAATGATTGGGGAAGAGCACC
	ATG
hsa-mir-029a-	ATGACTGATTTCTTTTGGTGTTCAGAGTCAATATAATTTTCTAGCACCATCTG	68
prec	AAATCGGTTAT
hsa-mir-029c-	ACCACTGGCCCATCTCTTACACAGGCTGACCGATTTCTCCTGGTGTTCAGAGT	69
prec	CTGTTTTTGTCTAGCACCATTTGAAATCGGTTATGATGTAGGGGGAAAAGCA
	GCAGC
hsa-mir-030a-	GCGACTGTAAACATCCTCGACTGGAAGCTGTGAAGCCACAGATGGGCTTTCA	70
prec	GTCGGATGTTTGCAGCTGC
hsa-mir-030b-	ATGTAAACATCCTACACTCAGCTGTAATACATGGATTGGCTGGGAGGTGGAT	71
prec	GTTTACGT
hsa-mir-030b-	ACCAAGTTTCAGTTCATGTAAACATCCTACACTCAGCTGTAATACATGGATT	72
prec	GGCTGGGAGGTGGATGTTTACTTCAGCTGACTTGGA
hsa-mir-030c-	AGATACTGTAAACATCCTACACTCTCAGCTGTGGAAAGTAAGAAAGCTGGG	73
prec	AGAAGGCTGTTTACTCTTTCT
hsa-mir-030d-	GTTGTTGTAAACATCCCCGACTGGAAGCTGTAAGACACAGCTAAGCTTTCAG	74
prec	TCAGATGTTTGCTGCTAC
hsa-mir-031-prec	GGAGAGGAGGCAAGATGCTGGCATAGCTGTTGAACTGGGAACCTGCTATGC	75
	CAACATATTGCCATCTTTCC
hsa-mir-032-prec	GGAGATATTGCACATTACTAAGTTGCATGTTGTCACGGCCTCAATGCAATTT	76
	AGTGTGTGTGATATTTTC
hsa-mir-033b-	GGGGGCCGAGAGAGGCGGGCGGCCCCGCGGTGCATTGCTGTTGCATTGCAC	77
prec	GTGTGTGAGGCGGGTGCAGTGCCTCGGCAGTGCAGCCCGGAGCCGGCCCCT
	GGCACCAC
hsa-mir-033-prec	CTGTGGTGCATTGTAGTTGCATTGCATGTTCTGGTGGTACCCATGCAATGTTT	78
	CCACAGTGCATCACAG
hsa-mir-034-prec	GGCCAGCTGTGAGTGTTTCTTTGGCAGTGTCTTAGCTGGTTGTTGTGAGCAAT	79
	AGTAAGGAAGCAATCAGCAAGTATACTGCCCTAGAAGTGCTGCACGTTGTG
	GGGCCC
hsa-mir-091-	TCAGAATAATGTCAAAGTGCTTACAGTGCAGGTAGTGATATGTGCATCTACT	80
prec-13	GCAGTGAAGGCACTTGTAGCATTATGGTGA
hsa-mir-092-	CTTTCTACACAGGTTGGGATCGGTTGCAATGCTGTGTTTCTGTATGGTATTGC	81
prec-13 = 092-1	ACTTGTCCCGGCCTGTTGAGTTTGG
hsa-mir-092-	TCATCCCTGGGTGGGGATTTGTTGCATTACTTGTGTTCTATATAAAGTATTGC	82
prec-X = 092-2	ACTTGTCCCGGCCTGTGGAAGA
hsa-mir-093-	CTGGGGGCTCCAAAGTGCTGTTCGTGCAGGTAGTGTGATTACCCAACCTACT	83
prec-7.1 = 093-1	GCTGAGCTAGCACTTCCCGAGCCCCCGG
hsa-mir-093-	CTGGGGGCTCCAAAGTGCTGTTCGTGCAGGTAGTGTGATTACCCAACCTACT	84
prec-7.2 = 093-2	GCTGAGCTAGCACTTCCCGAGCCCCCGG
hsa-mir-095-	AACACAGTGGGCACTCAATAAATGTCTGTTGAATTGAAATGCGTTACATTCA	85
prec-4	ACGGGTATTTATTGAGCACCCACTCTGTG
hsa-mir-096-	TGGCCGATTTTGGCACTAGCACATTTTTGCTTGTGTCTCTCCGCTCTGAGCAA	86
prec-7	TCATGTGCAGTGCCAATATGGGAAA
hsa-mir-098-	GTGAGGTAGTAAGTTGTATTGTTGTGGGGTAGGGATATTAGGCCCCAATTAG	87
prec-X	AAGATAACTATACAACTTACTACTTTCC
hsa-mir-099b-	GGCACCCACCCGTAGAACCGACCTTGCGGGGCCTTCGCCGCACACAAGCTCG	88
prec-19	TGTCTGTGGGTCCGTGTC
hsa-mir-099-	CCCATTGGCATAAACCCGTAGATCCGATCTTGTGGTGAAGTGGACCGCACAA	89
prec-21	GCTCGCTTCTATGGGTCTGTGTCAGTGTG
hsa-mir-100-1/2-	AAGAGAGAAGATATTGAGGCCTGTTGCCACAAACCCGTAGATCCGAACTTGT	90
prec	GGTATTAGTCCGCACAAGCTTGTATCTATAGGTATGTGTCTGTTAGGCAATCT
	CAC
hsa-mir-100-	CCTGTTGCCACAAACCCGTAGATCCGAACTTGTGGTATTAGTCCGCACAAGC	91
prec-11	TTGTATCTATAGGTATGTGTCTGTTAGG
hsa-mir-101-1/2-	AGGCTGCCCTGGCTCAGTTATCACAGTGCTGATGCTGTCTATTCTAAAGGTA	92
prec	CAGTACTGTGATAACTGAAGGATGGCAGCCATCTTACCTTCCATCAGAGGAG
	CCTCAC
hsa-mir-101-prec	TCAGTTATCACAGTGCTGATGCTGTCCATTCTAAAGGTACAGTACTGTGATA	93
	ACTGA
hsa-mir-101-	TGCCCTGGCTCAGTTATCACAGTGCTGATGCTGTCTATTCTAAAGGTACAGTA	94
prec-1	CTGTGATAACTGAAGGATGGCA
hsa-mir-101-	TGTCCTTTTTCGGTTATCATGGTACCGATGCTGTATATCTGAAAGGTACAGTA	95
prec-9	CTGTGATAACTGAAGAATGGTG
hsa-mir-102-	CTTCTGGAAGCTGGTTTCACATGGTGGCTTAGATTTTTCCATCTTTGTATCTA	96
prec-1	GCACCATTTGAAATCAGTGTTTTAGGAG
hsa-mir-102-	CTTCAGGAAGCTGGTTTCATATGGTGGTTTAGATTTAAATAGTGATTGTCTAG	97
prec-7.1	CACCATTTGAAATCAGTGTTCTTGGGGG
hsa-mir-102-	CTTCAGGAAGCTGGTTTCATATGGTGGTTTAGATTTAAATAGTGATTGTCTAG	98
prec-7.2	CACCATTTGAAATCAGTGTTCTTGGGGG
hsa-mir-103-2-	TTGTGCTTTCAGCTTCTTTACAGTGCTGCCTTGTAGCATTCAGGTCAAGCAAC	99
prec	ATTGTACAGGGCTATGAAAGAACCA
hsa-mir-103-	TTGTGCTTTCAGCTTCTTTACAGTGCTGCCTTGTAGCATTCAGGTCAAGCAAC	100
prec-20	ATTGTACAGGGCTATGAAAGAACCA
hsa-mir-103-	TACTGCCCTCGGCTTCTTTACAGTGCTGCCTTGTTGCATATGGATCAAGCAGC	101
prec-5 = 103-1	ATTGTACAGGGCTATGAAGGCATTG
hsa-mir-104-	AAATGTCAGACAGCCCATCGACTGGTGTTGCCATGAGATTCAACAGTCAACA	102
prec-17	TCAGTCTGATAAGCTACCCGACAAGG
hsa-mir-105-	TGTGCATCGTGGTCAAATGCTCAGACTCCTGTGGTGGCTGCTCATGCACCAC	103
prec-X.1 = 105-1	GGATGTTTGAGCATGTGCTACGGTGTCTA
hsa-mir-105-	TGTGCATCGTGGTCAAATGCTCAGACTCCTGTGGTGGCTGCTCATGCACCAC	104
prec-X.2 = 105-2	GGATGTTTGAGCATGTGCTACGGTGTCTA
hsa-mir-106-	CCTTGGCCATGTAAAAGTGCTTACAGTGCAGGTAGCTTTTTGAGATCTACTG	105
prec-X	CAATGTAAGCACTTCTTACATTACCATGG
hsa-mir-107-	CTCTCTGCTTTCAGCTTCTTTACAGTGTTGCCTTGTGGCATGGAGTTCAAGCA	106
prec-10	GCATTGTACAGGGCTATCAAAGCACAGA
hsa-mir-122a-	CCTTAGCAGAGCTGTGGAGTGTGACAATGGTGTTTGTGTCTAAACTATCAAA	107
prec	CGCCATTATCACACTAAATAGCTACTGCTAGGC
hsa-mir-122a-	AGCTGTGGAGTGTGACAATGGTGTTTGTGTCCAAACTATCAAACGCCATTAT	108
prec	CACACTAAATAGCT
hsa-mir-123-prec	ACATTATTACTTTTGGTACGCGCTGTGACACTTCAAACTCGTACCGTGAGTAA	109
	TAATGCGC
hsa-mir-124a-1-	tccttcctCAGGAGAAAGGCCTCTCTCTCCGTGTTCACAGCGGACCTTGATTTAAA	110
prec	TGTCCATACAATTAAGGCACGCGGTGAATGCCAAGAATGGGGCT
hsa-mir-124a-1-	AGGCCTCTCTCTCCGTGTTCACAGCGGACCTTGATTTAAATGTCCATACAATT	111
prec	AAGGCACGCGGTGAATGCCAAGAATGGGGCTG
hsa-mir-124a-2-	ATCAAGATTAGAGGCTCTGCTCTCCGTGTTCACAGCGGACCTTGATTTAATGT	112
prec	CATACAATTAAGGCACGCGGTGAATGCCAAGAGCGGAGCCTACGGCTGCAC
	TTGAAG
hsa-mir-124a-3-	CCCGCCCCAGCCCTGAGGGCCCCTCTGCGTGTTCACAGCGGACCTTGATTTA	113
prec	ATGTCTATACAATTAAGGCACGCGGTGAATGCCAAGAGAGGCGCCTCCGCC
	GCTCCTT
hsa-mir-124a-3-	TGAGGGCCCCTCTGCGTGTTCACAGCGGACCTTGATTTAATGTCTATACAATT	114
prec	AAGGCACGCGGTGAATGCCAAGAGAGGCGCCTCC
hsa-mir-124a-	CTCTGCGTGTTCACAGCGGACCTTGATTTAATGTCTATACAATTAAGGCACG	115
prec	CGGTGAATGCCAAGAG
hsa-mir-124b-	CTCTCCGTGTTCACAGCGGACCTTGATTTAATGTCATACAATTAAGGCACGC	116
prec	GGTGAATGCCAAGAG
hsa-mir-125a-	TGCCAGTCTCTAGGTCCCTGAGACCCTTTAACCTGTGAGGACATCCAGGGTC	117
prec	ACAGGTGAGGTTCTTGGGAGCCTGGCGTCTGGCC
hsa-mir-125a-	GGTCCCTGAGACCCTTTAACCTGTGAGGACATCCAGGGTCACAGGTGAGGTT	118
prec	CTTGGGAGCCTGG
hsa-mir-125b-1	ACATTGTTGCGCTCCTCTCAGTCCCTGAGACCCTAACTTGTGATGTTTACCGT	119
	TTAAATCCACGGGTTAGGCTCTTGGGAGCTGCGAGTCGTGCTTTTGCATCCTG
	GA
hsa-mir-125b-1	TGCGCTCCTCTCAGTCCCTGAGACCCTAACTTGTGATGTTTACCGTTTAAATC	120
	CACGGGTTAGGCTCTTGGGAGCTGCGAGTCGTGCT
hsa-mir-125b-2-	ACCAGACTTTTCCTAGTCCCTGAGACCCTAACTTGTGAGGTATTTTAGTAACA	121
prec	TCACAAGTCAGGCTCTTGGGACCTAGGCGGAGGGGA
hsa-mir-125b-2-	CCTAGTCCCTGAGACCCTAACTTGTGAGGTATTTTAGTAACATCACAAGTCA	122
prec	GGCTCTTGGGACCTAGGC
hsa-mir-126-prec	CGCTGGCGACGGGACATTATTACTTTTGGTACGCGCTGTGACACTTCAAACT	123
	CGTACCGTGAGTAATAATGCGCCGTCCACGGCA
hsa-mir-126-prec	ACATTATTACTTTTGGTACGCGCTGTGACACTTCAAACTCGTACCGTGAGTAA	124
	TAATGCGC
hsa-mir-127-prec	TGTGATCACTGTCTCCAGCCTGCTGAAGCTCAGAGGGCTCTGATTCAGAAAG	125
	ATCATCGGATCCGTCTGAGCTTGGCTGGTCGGAAGTCTCATCATC
hsa-mir-127-prec	CCAGCCTGCTGAAGCTCAGAGGGCTCTGATTCAGAAAGATCATCGGATCCGT	126
	CTGAGCTTGGCTGGTCGG
hsa-mir-128a-	TGAGCTGTTGGATTCGGGGCCGTAGCACTGTCTGAGAGGTTTACATTTCTCA	127
prec	CAGTGAACCGGTCTCTTTTTCAGCTGCTTC
hsa-mir-128b-	GCCCGGCAGCCACTGTGCAGTGGGAAGGGGGGCCGATACACTGTACGAGAG	128
prec	TGAGTAGCAGGTCTCACAGTGAACCGGTCTCTTTCCCTACTGTGTCACACTCC
	TAATGG
hsa-mir-128-prec	GTTGGATTCGGGGCCGTAGCACTGTCTGAGAGGTTTACATTTCTCACAGTGA	129
	ACCGGTCTCTTTTTCAGC
hsa-mir-129-prec	TGGATCTTTTTGCGGTCTGGGCTTGCTGTTCCTCTCAACAGTAGTCAGGAAGC	130
	CCTTACCCCAAAAAGTATCTA
hsa-mir-130a-	TGCTGCTGGCCAGAGCTCTTTTCACATTGTGCTACTGTCTGCACCTGTCACTA	131
prec	GCAGTGCAATGTTAAAAGGGCATTGGCCGTGTAGTG
hsa-mir-131-1-	gccaggaggcggGGTTGGTTGTTATCTTTGGTTATCTAGCTGTATGAGTGGTGTGG	132
prec	AGTCTTCATAAAGCTAGATAACCGAAAGTAAAAATAACCCCATACACTGCGC
	AG
hsa-mir-131-3-	CACGGCGCGGCAGCGGCACTGGCTAAGGGAGGCCCGTTTCTCTCTTTGGTTA	133
prec	TCTAGCTGTATGAGTGCCACAGAGCCGTCATAAAGCTAGATAACCGAAAGTA
	GAAATG
hsa-mir-131-prec	GTTGTTATCTTTGGTTATCTAGCTGTATGAGTGTATTGGTCTTCATAAAGCTA	134
	GATAACCGAAAGTAAAAAC
hsa-mir-132-prec	CCGCCCCCGCGTCTCCAGGGCAACCGTGGCTTTCGATTGTTACTGTGGGAAC	135
	TGGAGGTAACAGTCTACAGCCATGGTCGCCCCGCAGCACGCCCACGCGC
hsa-mir-132-prec	GGGCAACCGTGGCTTTCGATTGTTACTGTGGGAACTGGAGGTAACAGTCTAC	136
	AGCCATGGTCGCCC
hsa-mir-133a-1	ACAATGCTTTGCTAGAGCTGGTAAAATGGAACCAAATCGCCTCTTCAATGGA	137
	TTTGGTCCCCTTCAACCAGCTGTAGCTATGCATTGA
hsa-mir-133a-2	GGGAGCCAAATGCTTTGCTAGAGCTGGTAAAATGGAACCAAATCGACTGTCC	138
	AATGGATTTGGTCCCCTTCAACCAGCTGTAGCTGTGCATTGATGGCGCCG
hsa-mir-133-prec	GCTAGAGCTGGTAAAATGGAACCAAATCGCCTCTTCAATGGATTTGGTCCCC	139
	TTCAACCAGCTGTAGC
hsa-mir-134-prec	CAGGGTGTGTGACTGGTTGACCAGAGGGGCATGCACTGTGTTCACCCTGTGG	140
	GCCACCTAGTCACCAACCCTC
hsa-mir-134-prec	AGGGTGTGTGACTGGTTGACCAGAGGGGCATGCACTGTGTTCACCCTGTGGG	141
	CCACCTAGTCACCAACCCT
hsa-mir-135-1-	AGGCCTCGCTGTTCTCTATGGCTTTTTATTCCTATGTGATTCTACTGCTCACTC	142
prec	ATATAGGGATTGGAGCCGTGGCGCACGGCGGGGACA
hsa-mir-135-2-	AGATAAATTCACTCTAGTGCTTTATGGCTTTTTATTCCTATGTGATAGTAATA	143
prec	AAGTCTCATGTAGGGATGGAAGCCATGAAATACATTGTGAAAAATCA
hsa-mir-135-prec	CTATGGCTTTTTATTCCTATGTGATTCTACTGCTCACTCATATAGGGATTGGA	144
	GCCGTGG
hsa-mir-136-prec	TGAGCCCTCGGAGGACTCCATTTGTTTTGATGATGGATTCTTATGCTCCATCA	145
	TCGTCTCAAATGAGTCTTCAGAGGGTTCT
hsa-mir-136-prec	GAGGACTCCATTTGTTTTGATGATGGATTCTTATGCTCCATCATCGTCTCAAA	146
	TGAGTCTTC
hsa-mir-137-prec	CTTCGGTGACGGGTATTCTTGGGTGGATAATACGGATTACGTTGTTATTGCTT	147
	AAGAATACGCGTAGTCGAGG
hsa-mir-138-1-	CCCTGGCATGGTGTGGTGGGGCAGCTGGTGTTGTGAATCAGGCCGTTGCCAA	148
prec	TCAGAGAACGGCTACTTCACAACACCAGGGCCACACCACACTACAGG
hsa-mir-138-2-	CGTTGCTGCAGCTGGTGTTGTGAATCAGGCCGACGAGCAGCGCATCCTCTTA	149
prec	CCCGGCTATTTCACGACACCAGGGTTGCATCA
hsa-mir-138-prec	CAGCTGGTGTTGTGAATCAGGCCGACGAGCAGCGCATCCTCTTACCCGGCTA	150
	TTTCACGACACCAGGGTTG
hsa-mir-139-prec	GTGTATTCTACAGTGCACGTGTCTCCAGTGTGGCTCGGAGGCTGGAGACGCG	151
	GCCCTGTTGGAGTAAC
hsa-mir-140	TGTGTCTCTCTCTGTGTCCTGCCAGTGGTTTTACCCTATGGTAGGTTACGTCA	152
	TGCTGTTCTACCACAGGGTAGAACCACGGACAGGATACCGGGGCACC
hsa-mir-140as-	TCCTGCCAGTGGTTTTACCCTATGGTAGGTTACGTCATGCTGTTCTACCACAG	153
prec	GGTAGAACCACGGACAGGA
hsa-mir-140s-	CCTGCCAGTGGTTTTACCCTATGGTAGGTTACGTCATGCTGTTCTACCACAGG	154
prec	GTAGAACCACGGACAGG
hsa-mir-141-prec	CGGCCGGCCCTGGGTCCATCTTCCAGTACAGTGTTGGATGGTCTAATTGTGA	155
	AGCTCCTAACACTGTCTGGTAAAGATGGCTCCCGGGTGGGTTC
hsa-mir-141-prec	GGGTCCATCTTCCAGTACAGTGTTGGATGGTCTAATTGTGAAGCTCCTAACA	156
	CTGTCTGGTAAAGATGGCCC
hsa-mir-142as-	ACCCATAAAGTAGAAAGCACTACTAACAGCACTGGAGGGTGTAGTGTTTCCT	157
prec	ACTTTATGGATG
hsa-mir-142-prec	GACAGTGCAGTCACCCATAAAGTAGAAAGCACTACTAACAGCACTGGAGGG	158
	TGTAGTGTTTCCTACTTTATGGATGAGTGTACTGTG
hsa-mir-142s-	ACCCATAAAGTAGAAAGCACTACTAACAGCACTGGAGGGTGTAGTGTTTCCT	159
prec	ACTTTATGGATG
hsa-mir-143-prec	GCGCAGCGCCCTGTCTCCCAGCCTGAGGTGCAGTGCTGCATCTCTGGTCAGT	160
	TGGGAGTCTGAGATGAAGCACTGTAGCTCAGGAAGAGAGAAGTTGTTCTGC
	AGC
hsa-mir-143-prec	CCTGAGGTGCAGTGCTGCATCTCTGGTCAGTTGGGAGTCTGAGATGAAGCAC	161
	TGTAGCTCAGG
hsa-mir-144-prec	TGGGGCCCTGGCTGGGATATCATCATATACTGTAAGTTTGCGATGAGACACT	162
	ACAGTATAGATGATGTACTAGTCCGGGCACCCCC
hsa-mir-144-prec	GGCTGGGATATCATCATATACTGTAAGTTTGCGATGAGACACTACAGTATAG	163
	ATGATGTACTAGTC
hsa-mir-145-prec	CACCTTGTCCTCACGGTCCAGTTTTCCCAGGAATCCCTTAGATGCTAAGATGG	164
	GGATTCCTGGAAATACTGTTCTTGAGGTCATGGTT
hsa-mir-145-prec	CTCACGGTCCAGTTTTCCCAGGAATCCCTTAGATGCTAAGATGGGGATTCCT	165
	GGAAATACTGTTCTTGAG
hsa-mir-146-prec	CCGATGTGTATCCTCAGCTTTGAGAACTGAATTCCATGGGTTGTGTCAGTGTC	166
	AGACCTCTGAAATTCAGTTCTTCAGCTGGGATATCTCTGTCATCGT
hsa-mir-146-prec	AGCTTTGAGAACTGAATTCCATGGGTTGTGTCAGTGTCAGACCTGTGAAATT	167
	CAGTTCTTCAGCT
hsa-mir-147-prec	AATCTAAAGACAACATTTCTGCACACACACCAGACTATGGAAGCCAGTGTGT	168
	GGAAATGCTTCTGCTAGATT
hsa-mir-148-prec	GAGGCAAAGTTCTGAGACACTCCGACTCTGAGTATGATAGAAGTCAGTGCAC	169
	TACAGAACTTTGTCTC
hsa-mir-149-prec	GCCGGCGCCCGAGCTCTGGCTCCGTGTCTTCACTCCCGTGCTTGTCCGAGGA	170
	GGGAGGGAGGGACGGGGGCTGTGCTGGGGCAGCTGGA
hsa-mir-149-prec	GCTCTGGCTCCGTGTCTTCACTCCCGTGCTTGTCCGAGGAGGGAGGGAGGGA	171
	C
hsa-mir-150-prec	CTCCCCATGGCCCTGTCTCCCAACCCTTGTACCAGTGCTGGGCTCAGACCCTG	172
	GTACAGGCCTGGGGGACAGGGACCTGGGGAC
hsa-mir-150-prec	CCCTGTCTCCCAACCCTTGTACCAGTGCTGGGCTCAGACCCTGGTACAGGCC	173
	TGGGGGACAGGG
hsa-mir-151-prec	CCTGCCCTCGAGGAGCTCACAGTCTAGTATGTCTCATCCCCTACTAGACTGA	174
	AGCTCCTTGAGGACAGG
hsa-mir-152-prec	TGTCCCCCCCGGCCCAGGTTCTGTGATACACTCCGACTCGGGCTCTGGAGCA	175
	GTCAGTGCATGACAGAACTTGGGCCCGGAAGGACC
hsa-mir-152-prec	GGCCCAGGTTCTGTGATACACTCCGACTCGGGCTCTGGAGCAGTCAGTGCAT	176
	GACAGAACTTGGGCCCCGG
hsa-mir-153-1-	CTCACAGCTGCCAGTGTCATTTTTGTGATCTGCAGCTAGTATTCTCACTCCAG	177
prec	TTGCATAGTCACAAAAGTGATCATTGGCAGGTGTGGC
hsa-mir-153-1-	tctctctctccctcACAGCTGCCAGTGTCATTGTCACAAAAGTGATCATTGGCAGGTG	178
prec	TGGCTGCTGCATG
hsa-mir-153-2-	AGCGGTGGCCAGTGTCATTTTTGTGATGTTGCAGCTAGTAATATGAGCCCAG	179
prec	TTGCATAGTCACAAAAGTGATCATTGGAAACTGTG
hsa-mir-153-2-	CAGTGTCATTTTTGTGATGTTGCAGCTAGTAATATGAGCCCAGTTGCATAGTC	180
prec	ACAAAAGTGATCATTG
hsa-mir-154-prec	GTGGTACTTGAAGATAGGTTATCCGTGTTGCCTTCGCTTTATTTGTGACGAAT	181
	CATACACGGTTGACCTATTTTTCAGTACCAA
hsa-mir-154-prec	GAAGATAGGTTATCCGTGTTGCCTTCGCTTTATTTGTGACGAATCATACACGG	182
	TTGACCTATTTTT
hsa-mir-155-prec	CTGTTAATGCTAATCGTGATAGGGGTTTTTGCCTCCAACTGACTCCTACATAT	183
	TAGCATTAACAG
hsa-mir-16-2-	CAATGTCAGCAGTGCCTTAGCAGCACGTAAATATTGGCGTTAAGATTCTAAA	184
prec	ATTATCTCCAGTATTAACTGTGCTGCTGAAGTAAGGTTGACCATACTCTACA
	GTTG
hsa-mir-181a-	AGAAGGGCTATCAGGCCAGCCTTCAGAGGACTCCAAGGAACATTCAACGCT	185
prec	GTCGGTGAGTTTGGGATTTGAAAAAACCACTGACCGTTGACTGTACCTTGGG
	GTCCTTA
hsa-mir-181b-	TGAGTTTTGAGGTTGCTTCAGTGAACATTCAACGCTGTCGGTGAGTTTGGAA	186
prec	TTAAAATCAAAACCATCGACCGTTGATTGTACCCTATGGCTAACCATCATCT
	ACTCCA
hsa-mir-181c-	CGGAAAATTTGCCAAGGGTTTGGGGGAACATTCAACCTGTCGGTGAGTTTGG	187
prec	GCAGCTCAGGCAAACCATCGACCGTTGAGTGGACCCTGAGGCCTGGAATTGC
	CATCCT
hsa-mir-182-as-	GAGCTGCTTGCCTCCCCCCGTTTTTGGCAATGGTAGAACTCACACTGGTGAG	188
prec	GTAACAGGATCCGGTGGTTCTAGACTTGCCAACTATGGGGCGAGGACTCAGC
	CGGCAC
hsa-mir-182-prec	TTTTTGGCAATGGTAGAACTCACACTGGTGAGGTAACAGGATCCGGTGGTTC	189
	TAGACTTGCCAACTATGG
hsa-mir-183-prec	CCGCAGAGTGTGACTCCTGTTCTGTGTATGGCACTGGTAGAATTCACTGTGA	190
	ACAGTCTCAGTCAGTGAATTACCGAAGGGCCATAAACAGAGCAGAGACAGA
	TCCACGA
hsa-mir-184-prec	CCAGTCACGTCCCCTTATCACTTTTCCAGCCCAGCTTTGTGACTGTAAGTGTT	191
	GGACGGAGAACTGATAAGGGTAGGTGATTGA
hsa-mir-184-prec	CCTTATCACTTTTCCAGCCCAGCTTTGTGACTGTAAGTGTTGGACGGAGAACT	192
	GATAAGGGTAGG
hsa-mir-185-prec	AGGGGGCGAGGGATTGGAGAGAAAGGCAGTTCCTGATGGTCCCCTCCCCAG	193
	GGGCTGGCTTTCCTCTGGTCCTTCCCTCCCA
hsa-mir-185-prec	AGGGATTGGAGAGAAAGGCAGTTCCTGATGGTCCCCTCCCCAGGGGCTGGCT	194
	TTCCTCTGGTCCTT
hsa-mir-186-prec	TGCTTGTAACTTTCCAAAGAATTCTCCTTTTGGGCTTTCTGGTTTTATTTTAAG	195
	CCCAAAGGTGAATTTTTTGGGAAGTTTGAGCT
hsa-mir-186-prec	ACTTTCCAAAGAATTCTCCTTTTGGGCTTTCTGGTTTTATTTTAAGCCCAAAG	196
	GTGAATTTTTTGGGAAGT
hsa-mir-187-prec	GGTCGGGCTCACCATGACACAGTGTGAGACTCGGGCTACAACACAGGACCC	197
	GGGGCGCTGCTCTGACCCCTCGTGTCTTGTGTTGCAGCCGGAGGGACGCAGG
	TCCGCA
hsa-mir-188-prec	TGCTCCCTCTCTCACATCCCTTGCATGGTGGAGGGTGAGCTTTCTGAAAACCC	198
	CTCCCACATGCAGGGTTTGCAGGATGGCGAGCC
hsa-mir-188-prec	TCTCACATCCCTTGCATGGTGGAGGGTGAGCTTTCTGAAAACCCCTCCCACA	199
	TGCAGGGTTTGCAGGA
hsa-mir-189-prec	CTGTCGATTGGACCCGCCCTCCGGTGCCTACTGAGCTGATATCAGTTCTCATT	200
	TTACACACTGGCTCAGTTCAGCAGGAACAGGAGTCGAGCCCTTGAGCAA
hsa-mir-189-prec	CTCCGGTGCCTACTGAGCTGATATCAGTTCTCATTTTACACACTGGCTCAGTT	201
	CAGCAGGAACAGGAG
hsa-mir-190-prec	TGCAGGCCTCTGTGTGATATGTTTGATATATTAGGTTGTTATTTAATCCAACT	202
	ATATATCAAACATATTCCTACAGTGTCTTGCC
hsa-mir-190-prec	CTGTGTGATATGTTTGATATATTAGGTTGTTATTTAATCCAACTATATATCAA	203
	ACATATTCCTACAG
hsa-mir-191-prec	CGGCTGGACAGCGGGCAACGGAATCCCAAAAGCAGCTGTTGTCTCCAGAGC	204
	ATTCCAGCTGCGCTTGGATTTCGTCCCCTGCTCTCCTGCCT
hsa-mir-191-prec	AGCGGGCAACGGAATCCCAAAAGCAGCTGTTGTCTCCAGAGCATTCCAGCTG	205
	CGCTTGGATTTCGTCCCCTGCT
hsa-mir-192-2/3	CCGAGACCGAGTGCACAGGGCTCTGACCTATGAATTGACAGCCAGTGCTCTC	206
	GTCTCCCCTCTGGCTGCCAATTCCATAGGTCACAGGTATGTTCGCCTCAATGC
	CAG
hsa-mir-192-prec	GCCGAGACCGAGTGCACAGGGCTCTGACCTATGAATTGACAGCCAGTGCTCT	207
	CGTCTCCCCTCTGGCTGCCAATTCCATAGGTCACAGGTATGTTCGCCTCAATG
	CCAGC
hsa-mir-193-prec	CGAGGATGGGAGCTGAGGGCTGGGTCTTTGCGGGCGAGATGAGGGTGTCGG	208
	ATCAACTGGCCTACAAAGTCCCAGTTCTCGGCCCCCG
hsa-mir-193-prec	GCTGGGTCTTTGCGGGCGAGATGAGGGTGTCGGATCAACTGGCCTACAAAGT	209
	CCCAGT
hsa-mir-194-prec	ATGGTGTTATCAAGTGTAACAGCAACTCCATGTGGACTGTGTACCAATTTCC	210
	AGTGGAGATGCTGTTACTTTTGATGGTTACCAA
hsa-mir-194-prec	GTGTAACAGCAACTCCATGTGGACTGTGTACCAATTTCCAGTGGAGATGCTG	211
	TTACTTTTGAT
hsa-mir-195-prec	AGCTTCCCTGGCTCTAGCAGCACAGAAATATTGGCACAGGGAAGCGAGTCTG	212
	CCAATATTGGCTGTGCTGCTCCAGGCAGGGTGGTG
hsa-mir-195-prec	TAGCAGCACAGAAATATTGGCACAGGGAAGCGAGTCTGCCAATATTGGCTG	213
	TGCTGCT
hsa-mir-196-1-	CTAGAGCTTGAATTGGAACTGCTGAGTGAATTAGGTAGTTTCATGTTGTTGG	214
prec	GCCTGGGTTTCTGAACACAACAACATTAAACCACCCGATTCACGGCAGTTAC
	TGCTCC
hsa-mir-196-1-	GTGAATTAGGTAGTTTCATGTTGTTGGGCCTGGGTTTCTGAACACAACAACA	215
prec	TTAAACCACCCGATTCAC
hsa-mir-196-2-	TGCTCGCTCAGCTGATCTGTGGCTTAGGTAGTTTCATGTTGTTGGGATTGAGT	216
prec	TTTGAACTCGGCAACAAGAAACTGCCTGAGTTACATCAGTCGGTTTTCGTCG
	AGGGC
hsa-mir-196-prec	GTGAATTAGGTAGTTTCATGTTGTTGGGCCTGGGTTTCTGAACACAACAACA	217
	TTAAACCACCCGATTCAC
hsa-mir-197-prec	GGCTGTGCCGGGTAGAGAGGGCAGTGGGAGGTAAGAGCTCTTCACCCTTCA	218
	CCACCTTCTCCACCCAGCATGGCC
hsa-mir-198-prec	TCATTGGTCCAGAGGGGAGATAGGTTCCTGTGATTTTTCCTTCTTCTCTATAG	219
	AATAAATGA
hsa-mir-199a-1-	GCCAACCCAGTGTTCAGACTACCTGTTCAGGAGGCTCTCAATGTGTACAGTA	220
prec	GTCTGCACATTGGTTAGGC
hsa-mir-199a-2-	AGGAAGCTTCTGGAGATCCTGCTCCGTCGCCCCAGTGTTCAGACTACCTGTT	221
prec	CAGGACAATGCCGTTGTACAGTAGTCTGCACATTGGTTAGACTGGGCAAGGG
	AGAGCA
hsa-mir-199b-	CCAGAGGACACCTCCACTCCGTCTACCCAGTGTTTAGACTATCTGTTCAGGA	222
prec	CTCCCAAATTGTACAGTAGTCTGCACATTGGTTAGGCTGGGCTGGGTTAGAC
	CCTCGG
hsa-mir-199s-	GCCAACCCAGTGTTCAGACTACCTGTTCAGGAGGCTCTCAATGTGTACAGTA	223
prec	GTCTGCACATTGGTTAGGC
hsa-mir-200a-	GCCGTGGCCATCTTACTGGGCAGCATTGGATGGAGTCAGGTCTCTAATACTG	224
prec	CCTGGTAATGATGACGGC
hsa-mir-200b-	CCAGCTCGGGCAGCCGTGGCCATCTTACTGGGCAGCATTGGATGGAGTCAGG	225
prec	TCTCTAATACTGCCTGGTAATGATGACGGCGGAGCCCTGCACG
hsa-mir-202-prec	GTTCCTTTTTCCTATGCATATACTTCTTTGAGGATCTGGCCTAAAGAGGTATA	226
	GGGCATGGGAAGATGGAGC
hsa-mir-203-prec	GTGTTGGGGACTCGCGCGCTGGGTCCAGTGGTTCTTAACAGTTCAACAGTTC	227
	TGTAGCGCAATTGTGAAATGTTTAGGACCACTAGACCCGGCGGGCGCGGCG
	ACAGCGA
hsa-mir-204-prec	GGCTACAGTCTTTCTTCATGTGACTCGTGGACTTCCCTTTGTCATCCTATGCC	228
	TGAGAATATATGAAGGAGGCTGGGAAGGCAAAGGGACGTTCAATTGTCATC
	ACTGGC
hsa-mir-205-prec	AAAGATCCTCAGACAATCCATGTGCTTCTCTTGTCCTTCATTCCACCGGAGTC	229
	TGTCTCATACCCAACCAGATTTCAGTGGAGTGAAGTTCAGGAGGCATGGAGC
	TGACA
hsa-mir-206-prec	TGCTTCCCGAGGCCACATGCTTCTTTATATCCCCATATGGATTACTTTGCTAT	230
	GGAATGTAAGGAAGTGTGTGGTTTCGGCAAGTG
hsa-mir-206-prec	AGGCCACATGCTTCTTTATATCCCCATATGGATTACTTTGCTATGGAATGTAA	231
	GGAAGTGTGTGGTTTT
hsa-mir-208-prec	TGACGGGCGAGCTTTTGGCCCGGGTTATACCTGATGCTCACGTATAAGACGA	232
	GCAAAAAGCTTGTTGGTCA
hsa-mir-210-prec	ACCCGGCAGTGCCTCCAGGCGCAGGGCAGCCCCTGCCCACCGCACACTGCGC	233
	TGCCCCAGACCCACTGTGCGTGTGACAGCGGCTGATCTGTGCCTGGGCAGCG
	CGACCC
hsa-mir-211-prec	TCACCTGGCCATGTGACTTGTGGGCTTCCCTTTGTCATCCTTCGCCTAGGGCT	234
	CTGAGCAGGGCAGGGACAGCAAAGGGGTGCTCAGTTGTCACTTCCCACAGC
	ACGGAG
hsa-mir-212-prec	CGGGGCACCCCGCCCGGACAGCGCGCCGGCACCTTGGCTCTAGACTGCTTAC	235
	TGCCCGGGCCGCCCTCAGTAACAGTCTCCAGTCACGGCCACCGACGCCTGGC
	CCCGCC
hsa-mir-213-prec	CCTGTGCAGAGATTATTTTTTAAAAGGTCACAATCAACATTCATTGCTGTCGG	236
	TGGGTTGAACTGTGTGGACAAGCTCACTGAACAATGAATGCAACTGTGGCCC
	CGCTT
hsa-mir-213-	GAGTTTTGAGGTTGCTTCAGTGAACATTCAACGCTGTCGGTGAGTTTGGAAT	237
prec-LIM	TAAAATCAAAACCATCGACCGTTGATTGTACCCTATGGCTAACCATCATCTA
	CTCC
hsa-mir-214-prec	GGCCTGGCTGGACAGAGTTGTCATGTGTCTGCCTGTCTACACTTGCTGTGCA	238
	GAACATCCGCTCACCTGTACAGCAGGCACAGACAGGCAGTCACATGACAAC
	CCAGCCT
hsa-mir-215-prec	ATCATTCAGAAATGGTATACAGGAAAATGACCTATGAATTGACAGACAATAT	239
	AGCTGAGTTTGTCTGTCATTTCTTTAGGCCAATATTCTGTATGACTGTGCTAC
	TTCAA
hsa-mir-216-prec	GATGGCTGTGAGTTGGCTTAATCTCAGCTGGCAACTGTGAGATGTTCATACA	240
	ATCCCTCACAGTGGTCTCTGGGATTATGCTAAACAGAGCAATTTCCTAGCCC
	TCACGA
hsa-mir-217-prec	AGTATAATTATTACATAGTTTTTGATGTCGCAGATACTGCATCAGGAACTGA	241
	TTGGATAAGAATCAGTCACCATCAGTTCCTAATGCATTGCCTTCAGCATCTA
	AACAAG
hsa-mir-218-1-	GTGATAATGTAGCGAGATTTTCTGTTGTGCTTGATCTAACCATGTGGTTGCGA	242
prec	GGTATGAGTAAAACATGGTTCCGTCAAGCACCATGGAACGTCACGCAGCTTT
	CTACA
hsa-mir-218-2-	GACCAGTCGCTGCGGGGCTTTCCTTTGTGCTTGATCTAACCATGTGGTGGAA	243
prec	CGATGGAAACGGAACATGGTTCTGTCAAGCACCGCGGAAAGCACCGTGCTC
	TCCTGCA
hsa-mir-219-prec	CCGCCCCGGGCCGCGGCTCCTGATTGTCCAAACGCAATTCTCGAGTCTATGG	244
	CTCCGGCCGAGAGTTGAGTCTGGACGTCCCGAGCCGCCGCCCCCAAACCTCG
	AGCGGG
hsa-mir-220-prec	GACAGTGTGGCATTGTAGGGCTCCACACCGTATCTGACACTTTGGGCGAGGG	245
	CACCATGCTGAAGGTGTTCATGATGCGGTCTGGGAACTCCTCACGGATCTTA
	CTGATG
hsa-mir-221-prec	TGAACATCCAGGTCTGGGGCATGAACCTGGCATACAATGTAGATTTCTGTGT	246
	TCGTTAGGCAACAGCTACATTGTCTGCTGGGTTTCAGGCTACCTGGAAACAT
	GTTCTC
hsa-mir-222-prec	GCTGCTGGAAGGTGTAGGTACCCTCAATGGCTCAGTAGCCAGTGTAGATCCT	247
	GTCTTTCGTAATCAGCAGCTACATCTGGCTACTGGGTCTCTGATGGCATCTTC
	TAGCT
hsa-mir-223-prec	CCTGGCCTCCTGCAGTGCCACGCTCCGTGTATTTGACAAGCTGAGTTGGACA	248
	CTCCATGTGGTAGAGTGTCAGTTTGTCAAATACCCCAAGTGCGGCACATGCT
	TACCAG
hsa-mir-224-prec	GGGCTTTCAAGTCACTAGTGGTTCCGTTTAGTAGATGATTGTGCATTGTTTCA	249
	AAATGGTGCCCTAGTGACTACAAAGCCC
hsA-mir-29b-	CTTCTGGAAGCTGGTTTCACATGGTGGCTTAGATTTTTCCATCTTTGTATCTA	250
1 = 102-prec1	GCACCATTTGAAATCAGTGTTTTAGGAG
hsA-mir-29b-	CTTCAGGAAGCTGGTTTCATATGGTGGTTTAGATTTAAATAGTGATTGTCTAG	251
2 = 102prec7.1 =	CACCATTTGAAATCAGTGTTCTTGGGGG
7.2
hsA-mir-29b-	CTTCAGGAAGCTGGTTTCATATGGTGGTTTAGATTTAAATAGTGATTGTCTAG	252
3 = 102prec7.1 =	CACCATTTGAAATCAGTGTTCTTGGGGG
7.2
hsa-mir-	GTGAGCGACTGTAAACATCCTCGACTGGAAGCTGTGAAGCCACAGATGGGC	253
30* = mir-097-	TTTCAGTCGGATGTTTGCAGCTGCCTACT
prec-6
mir-033b	ACCAAGTTTCAGTTCATGTAAACATCCTACACTCAGCTGTAATACATGGATT	254
	GGCTGGGAGGTGGATGTTTACTTCAGCTGACTTGGA
mir-101-	TGCCCTGGCTCAGTTATCACAGTGCTGATGCTGTCTATTCTAAAGGTACAGTA	255
precursor-9 = mir-	CTGTGATAACTGAAGGATGGCA
101-3
mir-108-1-small	ACACTGCAAGAACAATAAGGATTTTTAGGGGCATTATGACTGAGTCAGAAA	256
	ACACAGCTGCCCCTGAAAGTCCCTCATTTTTCTTGCTGT
mir-108-2-small	ACTGCAAGAGCAATAAGGATTTTTAGGGGCATTATGATAGTGGAATGGAAA	257
	CACATCTGCCCCCAAAAGTCCCTCATTTT
mir-123-prec =	CGCTGGCGACGGGACATTATTACTTTTGGTACGCGCTGTGACACTTCAAACT	258
mir-126-prec	CGTACCGTGAGTAATAATGCGCCGTCCACGGCA
mir-123-prec =	ACATTATTACTTTTGGTACGCGCTGTGACACTTCAAACTCGTACCGTGAGTAA	259
mir-126-prec	TAATGCGC
mir-129-1-prec	TGGATCTTTTTGCGGTCTGGGCTTGCTGTTCCTCTCAACAGTAGTCAGGAAGC	260
	CCTTACCCCAAAAAGTATCTA
mir-129-small-	TGCCCTTCGCGAATCTTTTTGCGGTCTGGGCTTGCTGTACATAACTCAATAGC	261
2 = 129b?	CGGAAGCCCTTACCCCAAAAAGCATTTGCGGAGGGCG
mir-133b-small	GCCCCCTGCTCTGGCTGGTCAAACGGAACCAAGTCCGTCTTCCTGAGAGGTT	262
	TGGTCCCCTTCAACCAGCTACAGCAGGG
mir-135-small-2	AGATAAATTCACTCTAGTGCTTTATGGCTTTTTATTCCTATGTGATAGTAATA	263
	AAGTCTCATGTAGGGATGGAAGCCATGAAATACATTGTGAAAAATCA
mir-148b-small	AAGCACGATTAGCATTTGAGGTGAAGTTCTGTTATACACTCAGGCTGTGGCT	264
	CTCTGAAAGTCAGTGCAT
mir-151-prec	CCTGTCCTCAAGGAGCTTCAGTCTAGTAGGGGATGAGACATACTAGACTGTG	265
	AGCTCCTCGAGGGCAGG
mir-155-	CTGTTAATGCTAATCGTGATAGGGGTTTTTGCCTCCAACTGACTCCTACATAT	266
prec(BIC)	TAGCATTAACAG
mir-156 = mir-	CCTAACACTGTCTGGTAAAGATGGCTCCCGGGTGGGTTCTCTCGGCAGTAAC	267
157 = overlap	CTTCAGGGAGCCCTGAAGACCATGGAGGAC
mir-141
mir-158-small =	GCCGAGACCGAGTGCACAGGGCT AGTGCTCT	268
mir-192	CGTCTCCCCTCTGGCTGCCAATTCCATAGGTCACAGGTATGTTCGCCTCAATG
	CCAGC
mir-159-1-small	TCCCGCCCCCTGTAACAGCAACTCCATGTGGAAGTGCCCACTGGTTCCAGTG	269
	GGGCTGCTGTTATCTGGGGCGAGGGCCA
mir-161-small	AAAGCTGGGTTGAGAGGGCGAAAAAGGATGAGGTGACTGGTCTGGGCTACG	270
	CTATGCTGCGGCGCTCGGG
mir-163-1b-	CATTGGCCTCCTAAGCCAGGGATTGTGGGTTCGAGTCCCACCCGGGGTAAAG	271
small	AAAGGCCGAATT
mir-163-3-small	CCTAAGCCAGGGATTGTGGGTTCGAGTCCCACCTGGGGTAGAGGTGAAAGTT	272
	CCTTTTACGGAATTTTTT
mir-175-	GGGCTTTCAAGTCACTAGTGGTTCCGTTTAGTAGATGATTGTGCATTGTTTCA	273
small = mir-224	AAATGGTGCCCTAGTGACTACAAAGCCC
mir-177- small	ACGCAAGTGTCCTAAGGTGAGCTCAGGGAGCACAGAAACCTCCAGTGGAAC	274
	AGAAGGGCAAAAGCTCATT
mir-180- small	CATGTGTCACTTTCAGGTGGAGTTTCAAGAGTCCCTTCCTGGTTCACCGTCTC	275
	CTTTGCTCTTCCACAAC
mir-187-prec	GGTCGGGCTCACCATGACACAGTGTGAGACTCGGGCTACAACACAGGACCC	276
	GGGGCGCTGCTCTGACCCCTCGTGTCTTGTGTTGCAGCCGGAGGGACGCAGG
	TCCGCA
mir-188-prec	TGCTCCCTCTCTCACATCCCTTGCATGGTGGAGGGTGAGCTTTCTGAAAACCC	277
	CTCCCACATGCAGGGTTTGCAGGATGGCGAGCC
mir-190-prec	TGCAGGCCTCTGTGTGATATGTTTGATATATTAGGTTGTTATTTAATCCAACT	278
	ATATATCAAACATATTCCTACAGTGTCTTGCC
mir-197-2	GTGCATGTGTATGTATGTGTGCATGTGCATGTGTATGTGTATGAGTGCATGC	279
	GTGTGTGC
mir-197-prec	GGCTGTGCCGGGTAGAGAGGGCAGTGGGAGGTAAGAGCTCTTCACCCTTCA	280
	CCACCTTCTCCACCCAGCATGGCC
mir-202-prec	GTTCCTTTTTCCTATGCATATACTTCTTTGAGGATCTGGCCTAAAGAGGTATA	281
	GGGCATGGGAAGATGGAGC
mir-294-1	CAATCTTCCTTTATCATGGTATTGATTTTTCAGTGCTTCCCTTTTGTGTGAGAG	282
(chr16)	AAGATA
mir-hes1	ATGGAGCTGCTCACCCTGTGGGCCTCAAATGTGGAGGAACTATTCTGATGTC	283
	CAAGTGGAAAGTGCTGCGACATTTGAGCGTCACCGGTGACGCCCATATCA
mir-hes2	GCATCCCCTCAGCCTGTGGCACTCAAACTGTGGGGGCACTTTCTGCTCTCTGG	284
	TGAAAGTGCCGCCATCTTTTGAGTGTTACCGCTTGAGAAGACTCAACC
mir-hes3	CGAGGAGCTCATACTGGGATACTCAAAATGGGGGCGCTTTCCTTTTTGTCTG	285
	TTACTGGGAAGTGCTTCGATTTTGGGGTGTCCCTGTTTGAGTAGGGCATC
hsa-mir-29b-1	CTTCAGGAAGCTGGTTTCATATGGTGGTTTAGATTTAAATAGTGATTGTCTAG	286
	CACCATTTGAAATCAGTGTTCTTGGGGG
*An underlined sequence within a precursor sequence represents a processed miR transcript. All sequences are human.

The level of at least one miR gene product can be measured in cells of a biological sample obtained from the subject. For example, a tissue sample can be removed from a subject suspected of having breast cancer associated with by conventional biopsy techniques. In another example, a blood sample can be removed from the subject, and white blood cells can be isolated for DNA extraction by standard techniques. The blood or tissue sample is preferably obtained from the subject prior to initiation of radiotherapy, chemotherapy or other therapeutic treatment. A corresponding control tissue or blood sample can be obtained from unaffected tissues of the subject, from a normal human individual or population of normal individuals, or from cultured cells corresponding to the majority of cells in the subject's sample. The control tissue or blood sample is then processed along with the sample from the subject, so that the levels of miR gene product produced from a given miR gene in cells from the subject's sample can be compared to the corresponding miR gene product levels from cells of the control sample.

An alteration (i.e., an increase or decrease) in the level of a miR gene product in the sample obtained from the subject, relative to the level of a corresponding miR gene product in a control sample, is indicative of the presence of breast cancer in the subject. In one embodiment, the level of the at least one miR gene product in the test sample is greater than the level of the corresponding miR gene product in the control sample (i.e., expression of the miR gene product is “up-regulated”). As used herein, expression of a miR gene product is “up-regulated” when the amount of miR gene product in a cell or tissue sample from a subject is greater than the amount the same gene product in a control cell or tissue sample. In another embodiment, the level of the at least one miR gene product in the test sample is less than the level of the corresponding miR gene product in the control sample (i.e., expression of the miR gene product is “down-regulated”). As used herein, expression of a miR gene is “down-regulated” when the amount of miR gene product produced from that gene in a cell or tissue sample from a subject is less than the amount produced from the same gene in a control cell or tissue sample. The relative miR gene expression in the control and normal samples can be determined with respect to one or more RNA expression standards. The standards can comprise, for example, a zero miR gene expression level, the miR gene expression level in a standard cell line, or the average level of miR gene expression previously obtained for a population of normal human controls.

The level of a miR gene product in a sample can be measured using any technique that is suitable for detecting RNA expression levels in a biological sample. Suitable techniques for determining RNA expression levels in cells from a biological sample (for example, Northern blot analysis, RT-PCR, in situ hybridization) are well known to those of skill in the art. In a particular embodiment, the level of at least one miR gene product is detected using Northern blot analysis. For example, total cellular RNA can be purified from cells by homogenization in the presence of nucleic acid extraction buffer, followed by centrifugation. Nucleic acids are precipitated, and DNA is removed by treatment with DNase and precipitation. The RNA molecules are then separated by gel electrophoresis on agarose gels according to standard techniques, and transferred to nitrocellulose filters. The RNA is then immobilized on the filters by heating. Detection and quantification of specific RNA is accomplished using appropriately labeled DNA or RNA probes complementary to the RNA in question. See, for example, Molecular Cloning: A Laboratory Manual, J. Sambrook et al., eds., 2nd edition, Cold Spring Harbor Laboratory Press, 1989, Chapter 7, the entire disclosure of which is incorporated by reference.

Suitable probes for Northern blot hybridization of a given miR gene product can be produced from the nucleic acid sequences provided in Table 1. Methods for preparation of labeled DNA and RNA probes, and the conditions for hybridization thereof to target nucleotide sequences, are described in Molecular Cloning: A Laboratory Manual, J. Sambrook et al., eds., 2nd edition, Cold Spring Harbor Laboratory Press, 1989, Chapters 10 and 11, the disclosures of which are incorporated herein by reference.

For example, the nucleic acid probe can be labeled with, for example, a radionuclide, such as ³H, ³²P, ³³P, ¹⁴C, or ³⁵S; a heavy metal; or a ligand capable of functioning as a specific binding pair member for a labeled ligand (for example, biotin, avidin or an antibody), a fluorescent molecule, a chemiluminescent molecule, an enzyme or the like.

Probes can be labeled to high specific activity by either the nick translation method of Rigby et al. (1977), J. Mol. Biol. 113:237-251 or by the random priming method of Fienberg et al. (1983), Anal. Biochem. 132:6-13, the entire disclosures of which are incorporated herein by reference. The latter is the method of choice for synthesizing ³²P-labeled probes of high specific activity from single-stranded DNA or from RNA templates. For example, by replacing preexisting nucleotides with highly radioactive nucleotides according to the nick translation method, it is possible to prepare ³²P-labeled nucleic acid probes with a specific activity well in excess of 10⁸ cpm/microgram. Autoradiographic detection of hybridization can then be performed by exposing hybridized filters to photographic film. Densitometric scanning of the photographic films exposed by the hybridized filters provides an accurate measurement of miR gene transcript levels. Using another approach, miR gene transcript levels can be quantified by computerized imaging systems, such the Molecular Dynamics 400-B 2D Phosphorimager available from Amersham Biosciences, Piscataway, N.J.

Where radionuclide labeling of DNA or RNA probes is not practical, the random-primer method can be used to incorporate an analogue, for example, the dTTP analogue 5-(N—(N-biotinyl-epsilon-aminocaproyl)-3-aminoallyl)deoxyuridine triphosphate, into the probe molecule. The biotinylated probe oligonucleotide can be detected by reaction with biotin-binding proteins, such as avidin, streptavidin, and antibodies (for example, anti-biotin antibodies) coupled to fluorescent dyes or enzymes that produce color reactions.

In addition to Northern and other RNA hybridization techniques, determining the levels of RNA transcripts can be accomplished using the technique of in situ hybridization. This technique requires fewer cells than the Northern blotting technique, and involves depositing whole cells onto a microscope cover slip and probing the nucleic acid content of the cell with a solution containing radioactive or otherwise labeled nucleic acid (for example, cDNA or RNA) probes. This technique is particularly well-suited for analyzing tissue biopsy samples from subjects. The practice of the in situ hybridization technique is described in more detail in U.S. Pat. No. 5,427,916, the entire disclosure of which is incorporated herein by reference. Suitable probes for in situ hybridization of a given miR gene product can be produced from the nucleic acid sequences provided in Table 1, as described above.

The relative number of miR gene transcripts in cells can also be determined by reverse transcription of miR gene transcripts, followed by amplification of the reverse-transcribed transcripts by polymerase chain reaction (RT-PCR). The levels of miR gene transcripts can be quantified in comparison with an internal standard, for example, the level of mRNA from a “housekeeping” gene present in the same sample. A suitable “housekeeping” gene for use as an internal standard includes, for example, myosin or glyceraldehyde-3-phosphate dehydrogenase (G3PDH). The methods for quantitative RT-PCR and variations thereof are within the skill in the art.

In some instances, it may be desirable to simultaneously determine the expression level of a plurality of different miR gene products in a sample. In other instances, it may be desirable to determine the expression level of the transcripts of all known miR genes correlated with a cancer. Assessing cancer-specific expression levels for hundreds of miR genes is time consuming and requires a large amount of total RNA (at least 20 μg for each Northern blot) and autoradiographic techniques that require radioactive isotopes.

To overcome these limitations, an oligolibrary, in microchip format (i.e., a microarray), may be constructed containing a set of probe oligodeoxynucleotides that are specific for a set of miR genes. Using such a microarray, the expression level of multiple microRNAs in a biological sample can be determined by reverse transcribing the RNAs to generate a set of target oligodeoxynucleotides, and hybridizing them to probe oligodeoxynucleotides on the microarray to generate a hybridization, or expression, profile. The hybridization profile of the test sample can then be compared to that of a control sample to determine which microRNAs have an altered expression level in breast cancer cells. As used herein, “probe oligonucleotide” or “probe oligodeoxynucleotide” refers to an oligonucleotide that is capable of hybridizing to a target oligonucleotide. “Target oligonucleotide” or “target oligodeoxynucleotide” refers to a molecule to be detected (for example, via hybridization). By “miR-specific probe oligonucleotide” or “probe oligonucleotide specific for a miR” is meant a probe oligonucleotide that has a sequence selected to hybridize to a specific miR gene product, or to a reverse transcript of the specific miR gene product.

An “expression profile” or “hybridization profile” of a particular sample is essentially a fingerprint of the state of the sample; while two states may have any particular gene similarly expressed, the evaluation of a number of genes simultaneously allows the generation of a gene expression profile that is unique to the state of the cell. That is, normal tissue may be distinguished from breast cancer tissue, and within breast cancer tissue, different prognosis states (good or poor long term survival prospects, for example) may be determined. By comparing expression profiles of breast cancer tissue in different states, information regarding which genes are important (including both up- and down-regulation of genes) in each of these states is obtained. The identification of sequences that are differentially expressed in breast cancer tissue or normal breast tissue, as well as differential expression resulting in different prognostic outcomes, allows the use of this information in a number of ways. For example, a particular treatment regime may be evaluated (for example, to determine whether a chemotherapeutic drug act to improve the long-term prognosis in a particular patient). Similarly, diagnosis may be done or confirmed by comparing patient samples with the known expression profiles. Furthermore, these gene expression profiles (or individual genes) allow screening of drug candidates that suppress the breast cancer expression profile or convert a poor prognosis profile to a better prognosis profile.

Accordingly, the invention provides methods of diagnosing whether a subject has, or is at risk for developing, breast cancer, comprising reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligo-deoxynucleotides, hybridizing the target oligo-deoxynucleotides to a microarray comprising miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample, wherein an alteration in the signal of at least one miRNA is indicative of the subject either having, or being at risk for developing, breast cancer. In one embodiment, the microarray comprises miRNA-specific probe oligonucleotides for a substantial portion of the human miRNome. In a particular embodiment, the microarray comprises miRNA-specific probe oligo-nucleotides for one or more miRNAs selected from the group consisting of miR-125b, miR-145, miR-21, miR-155, miR-10b, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, miR-213, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, let-7i (let-7d-v2), miR-101-1, miR-122a, miR-128b, miR-136, miR-143, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210 and combinations thereof. In a further embodiment, the at least one miR gene product is selected from the group consisting of miR-125b, miR-145, miR-21, miR-155, miR-10b and combinations thereof.

The microarray can be prepared from gene-specific oligonucleotide probes generated from known miRNA sequences. The array may contain two different oligonucleotide probes for each miRNA, one containing the active, mature sequence and the other being specific for the precursor of the miRNA. The array may also contain controls, such as one or more mouse sequences differing from human orthologs by only a few bases, which can serve as controls for hybridization stringency conditions. tRNAs from both species may also be printed on the microchip, providing an internal, relatively stable, positive control for specific hybridization. One or more appropriate controls for non-specific hybridization may also be included on the microchip. For this purpose, sequences are selected based upon the absence of any homology with any known miRNAs.

The microarray may be fabricated using techniques known in the art. For example, probe oligonucleotides of an appropriate length, for example, 40 nucleotides, are 5′-amine modified at position C6 and printed using commercially available microarray systems, for example, the GeneMachine OmniGrid™ 100 Microarrayer and Amersham CodeLink™ activated slides. Labeled cDNA oligomer corresponding to the target RNAs is prepared by reverse transcribing the target RNA with labeled primer. Following first strand synthesis, the RNA/DNA hybrids are denatured to degrade the RNA templates. The labeled target cDNAs thus prepared are then hybridized to the microarray chip under hybridizing conditions, for example, 6×SSPE/30% formamide at 25° C. for 18 hours, followed by washing in 0.75×TNT at 37° C. for 40 minutes. At positions on the array where the immobilized probe DNA recognizes a complementary target cDNA in the sample, hybridization occurs. The labeled target cDNA marks the exact position on the array where binding occurs, allowing automatic detection and quantification. The output consists of a list of hybridization events, indicating the relative abundance of specific cDNA sequences, and therefore the relative abundance of the corresponding complementary miRs, in the patient sample. According to one embodiment, the labeled cDNA oligomer is a biotin-labeled cDNA, prepared from a biotin-labeled primer. The microarray is then processed by direct detection of the biotin-containing transcripts using, for example, Streptavidin-Alexa647 conjugate, and scanned utilizing conventional scanning methods. Image intensities of each spot on the array are proportional to the abundance of the corresponding miR in the patient sample.

The use of the array has several advantages for miRNA expression detection. First, the global expression of several hundred genes can be identified in the same sample at one time point. Second, through careful design of the oligonucleotide probes, expression of both mature and precursor molecules can be identified. Third, in comparison with Northern blot analysis, the chip requires a small amount of RNA, and provides reproducible results using 2.5 μg of total RNA. The relatively limited number of miRNAs (a few hundred per species) allows the construction of a common microarray for several species, with distinct oligonucleotide probes for each. Such a tool would allow for analysis of trans-species expression for each known miR under various conditions.

In addition to use for quantitative expression level assays of specific miRs, a microchip containing miRNA-specific probe oligonucleotides corresponding to a substantial portion of the miRNome, preferably the entire miRNome, may be employed to carry out miR gene expression profiling, for analysis of miR expression patterns. Distinct miR signatures can be associated with established disease markers, or directly with a disease state.

According to the expression profiling methods described herein, total RNA from a sample from a subject suspected of having a cancer (such as breast cancer) is quantitatively reverse transcribed to provide a set of labeled target oligodeoxynucleotides complementary to the RNA in the sample. The target oligodeoxynucleotides are then hybridized to a microarray comprising miRNA-specific probe oligonucleotides to provide a hybridization profile for the sample. The result is a hybridization profile for the sample representing the expression pattern of miRNA in the sample. The hybridization profile comprises the signal from the binding of the target oligodeoxynucleotides from the sample to the miRNA-specific probe oligonucleotides in the microarray. The profile may be recorded as the presence or absence of binding (signal vs. zero signal). More preferably, the profile recorded includes the intensity of the signal from each hybridization. The profile is compared to the hybridization profile generated from a normal, noncancerous, control sample. An alteration in the signal is indicative of the presence of the cancer in the subject.

Other techniques for measuring miR gene expression are also within the skill in the art, and include various techniques for measuring rates of RNA transcription and degradation.

The invention also provides methods of diagnosing a breast cancer associated with one or more prognostic markers, comprising measuring the level of at least one miR gene product in a breast cancer test sample from a subject and comparing the level of the at least one miR gene product in the breast cancer test sample to the level of a corresponding miR gene product in a control sample. An alteration (for example, an increase, a decrease) in the signal of at least one miRNA in the test sample relative to the control sample is indicative of the subject either having, or being at risk for developing, breast cancer associated with the one or more prognostic markers.

The breast cancer can be associated with one or more prognostic markers or features, including, a marker associated with an adverse (negative) prognosis, or a marker associated with a good (positive) prognosis. In certain embodiments, the breast cancer that is diagnosed using the methods described herein is associated with one or more adverse prognostic features selected from the group consisting of estrogen receptor expression, progesterone receptor expression, positive lymph node metastasis, high proliferative index, detectable p53 expression, advanced tumor stage, and high vascular invasion. Particular microRNAs whose expression is altered in breast cancer cells associated with each of these prognostic markers are described herein (see, for example, Example 3 and FIG. 4). In one embodiment, the level of the at least one miR gene product is measured by reverse transcribing RNA from a test sample obtained from the subject to provide a set of target oligodeoxynucleotides, hybridizing the target oligodeoxynucleotides to a microarray that comprises miRNA-specific probe oligonucleotides to provide a hybridization profile for the test sample, and comparing the test sample hybridization profile to a hybridization profile generated from a control sample.

Without wishing to be bound by any one theory, it is believed that alterations in the level of one or more miR gene products in cells can result in the deregulation of one or more intended targets for these miRs, which can lead to the formation of breast cancer. Therefore, altering the level of the miR gene product (for example, by decreasing the level of a miR that is up-regulated in breast cancer cells and/or by increasing the level of a miR that is down-regulated in cancer cells) may successfully treat the breast cancer. Examples of putative gene targets for miRNAs that are deregulated in breast cancer tissues are described herein (see, for example, Example 2 and Table 4).

Accordingly, the present invention encompasses methods of treating breast cancer in a subject, wherein at least one miR gene product is de-regulated (for example, down-regulated or up-regulated) in the cancer cells of the subject. When the at least one isolated miR gene product is down-regulated in the breast cancer cells, the method comprises administering an effective amount of the at least one isolated miR gene product, provided that the miR gene is not miR15 or miR16, such that proliferation of cancer cells in the subject is inhibited. When the at least one isolated miR gene product is up-regulated in the cancer cells, the method comprises administering to the subject an effective amount of at least one compound for inhibiting expression of the at least one miR gene, referred to herein as miR gene expression inhibition compounds, such that proliferation of breast cancer cells is inhibited.

The terms “treat”, “treating” and “treatment”, as used herein, refer to ameliorating symptoms associated with a disease or condition, for example, breast cancer, including preventing or delaying the onset of the disease symptoms, and/or lessening the severity or frequency of symptoms of the disease or condition. The terms “subject” and “individual” are defined herein to include animals, such as mammals, including but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent, or murine species. In a preferred embodiment, the animal is a human.

As used herein, an “effective amount” of an isolated miR gene product is an amount sufficient to inhibit proliferation of a cancer cell in a subject suffering from breast cancer. One skilled in the art can readily determine an effective amount of an miR gene product to be administered to a given subject, by taking into account factors, such as the size and weight of the subject; the extent of disease penetration; the age, health and sex of the subject; the route of administration; and whether the administration is regional or systemic.

For example, an effective amount of an isolated miR gene product can be based on the approximate weight of a tumor mass to be treated. The approximate weight of a tumor mass can be determined by calculating the approximate volume of the mass, wherein one cubic centimeter of volume is roughly equivalent to one gram. An effective amount of the isolated miR gene product based on the weight of a tumor mass can be in the range of about 10-500 micrograms/gram of tumor mass. In certain embodiments, the tumor mass can be at least about 10 micrograms/gram of tumor mass, at least about 60 micrograms/gram of tumor mass or at least about 100 micrograms/gram of tumor mass.

An effective amount of an isolated miR gene product can also be based on the approximate or estimated body weight of a subject to be treated. Preferably, such effective amounts are administered parenterally or enterally, as described herein. For example, an effective amount of the isolated miR gene product is administered to a subject can range from about 5-3000 micrograms/kg of body weight, from about 700-1000 micrograms/kg of body weight, or greater than about 1000 micrograms/kg of body weight.

One skilled in the art can also readily determine an appropriate dosage regimen for the administration of an isolated miR gene product to a given subject. For example, a miR gene product can be administered to the subject once (for example, as a single injection or deposition). Alternatively, a miR gene product can be administered once or twice daily to a subject for a period of from about three to about twenty-eight days, more particularly from about seven to about ten days. In a particular dosage regimen, a miR gene product is administered once a day for seven days. Where a dosage regimen comprises multiple administrations, it is understood that the effective amount of the miR gene product administered to the subject can comprise the total amount of gene product administered over the entire dosage regimen.

As used herein, an “isolated” miR gene product is one which is synthesized, or altered or removed from the natural state through human intervention. For example, a synthetic miR gene product, or a miR gene product partially or completely separated from the coexisting materials of its natural state, is considered to be “isolated.” An isolated miR gene product can exist in substantially-purified form, or can exist in a cell into which the miR gene product has been delivered. Thus, a miR gene product which is deliberately delivered to, or expressed in, a cell is considered an “isolated” miR gene product. A miR gene product produced inside a cell from a miR precursor molecule is also considered to be “isolated” molecule.

Isolated miR gene products can be obtained using a number of standard techniques. For example, the miR gene products can be chemically synthesized or recombinantly produced using methods known in the art. In one embodiment, miR gene products are chemically synthesized using appropriately protected ribonucleoside phosphoramidites and a conventional DNA/RNA synthesizer. Commercial suppliers of synthetic RNA molecules or synthesis reagents include, for example, Proligo (Hamburg, Germany), Dharmacon Research (Lafayette, Colo., U.S.A.), Pierce Chemical (part of Perbio Science, Rockford, Ill., U.S.A.), Glen Research (Sterling, Va., U.S.A.), ChemGenes (Ashland, Mass., U.S.A.) and Cruachem (Glasgow, UK).

Alternatively, the miR gene products can be expressed from recombinant circular or linear DNA plasmids using any suitable promoter. Suitable promoters for expressing RNA from a plasmid include, for example, the U6 or H1 RNA pol III promoter sequences, or the cytomegalovirus promoters. Selection of other suitable promoters is within the skill in the art. The recombinant plasmids of the invention can also comprise inducible or regulatable promoters for expression of the miR gene products in cancer cells.

The miR gene products that are expressed from recombinant plasmids can be isolated from cultured cell expression systems by standard techniques. The miR gene products which are expressed from recombinant plasmids can also be delivered to, and expressed directly in, the cancer cells. The use of recombinant plasmids to deliver the miR gene products to cancer cells is discussed in more detail below.

The miR gene products can be expressed from a separate recombinant plasmid, or they can be expressed from the same recombinant plasmid. In one embodiment, the miR gene products are expressed as RNA precursor molecules from a single plasmid, and the precursor molecules are processed into the functional miR gene product by a suitable processing system, including, but not limited to, processing systems extant within a cancer cell. Other suitable processing systems include, for example, the in vitro Drosophila cell lysate system (for example, as described in U.S. Published Patent Application No. 2002/0086356 to Tuschl et al., the entire disclosure of which are incorporated herein by reference) and the E. coli RNAse III system (for example, as described in U.S. Published Patent Application No. 2004/0014113 to Yang et al., the entire disclosure of which are incorporated herein by reference).

Selection of plasmids suitable for expressing the miR gene products, methods for inserting nucleic acid sequences into the plasmid to express the gene products, and methods of delivering the recombinant plasmid to the cells of interest are within the skill in the art. See, for example, Zeng et al. (2002), Molecular Cell 9:1327-1333; Tuschl (2002), Nat. Biotechnol, 20:446-448; Brummelkamp et al. (2002), Science 296:550-553; Miyagishi et al. (2002), Nat. Biotechnol. 20:497-500; Paddison et al. (2002), Genes Dev. 16:948-958; Lee et al. (2002), Nat. Biotechnol. 20:500-505; and Paul et al. (2002), Nat. Biotechnol. 20:505-508, the entire disclosures of which are incorporated herein by reference.

In one embodiment, a plasmid expressing the miR gene products comprises a sequence encoding a miR precursor RNA under the control of the CMV intermediate-early promoter. As used herein, “under the control” of a promoter means that the nucleic acid sequences encoding the miR gene product are located 3′ of the promoter, so that the promoter can initiate transcription of the miR gene product coding sequences.

The miR gene products can also be expressed from recombinant viral vectors. It is contemplated that the miR gene products can be expressed from two separate recombinant viral vectors, or from the same viral vector. The RNA expressed from the recombinant viral vectors can either be isolated from cultured cell expression systems by standard techniques, or can be expressed directly in cancer cells. The use of recombinant viral vectors to deliver the miR gene products to cancer cells is discussed in more detail below.

The recombinant viral vectors of the invention comprise sequences encoding the miR gene products and any suitable promoter for expressing the RNA sequences. Suitable promoters include, for example, the U6 or H1 RNA pol III promoter sequences, or the cytomegalovirus promoters. Selection of other suitable promoters is within the skill in the art. The recombinant viral vectors of the invention can also comprise inducible or regulatable promoters for expression of the miR gene products in a cancer cell.

Any viral vector capable of accepting the coding sequences for the miR gene products can be used; for example, vectors derived from adenovirus (AV); adeno-associated virus (AAV); retroviruses (for example, lentiviruses (LV), Rhabdoviruses, murine leukemia virus); herpes virus, and the like. The tropism of the viral vectors can be modified by pseudotyping the vectors with envelope proteins or other surface antigens from other viruses, or by substituting different viral capsid proteins, as appropriate.

For example, lentiviral vectors of the invention can be pseudotyped with surface proteins from vesicular stomatitis virus (VSV), rabies, Ebola, Mokola, and the like. AAV vectors of the invention can be made to target different cells by engineering the vectors to express different capsid protein serotypes. For example, an AAV vector expressing a serotype 2 capsid on a serotype 2 genome is called AAV 2/2. This serotype 2 capsid gene in the AAV 2/2 vector can be replaced by a serotype 5 capsid gene to produce an AAV 2/5 vector. Techniques for constructing AAV vectors that express different capsid protein serotypes are within the skill in the art; see, for example, Rabinowitz, J. E., et al. (2002), J. Virol. 76:791-801, the entire disclosure of which is incorporated herein by reference.

Selection of recombinant viral vectors suitable for use in the invention, methods for inserting nucleic acid sequences for expressing RNA into the vector, methods of delivering the viral vector to the cells of interest, and recovery of the expressed RNA products are within the skill in the art. See, for example, Dornburg (1995), Gene Therap. 2:301-310; Eglitis (1988), Biotechniques 6:608-614; Miller (1990), Hum. Gene Therap. 1:5-14; and Anderson (1998), Nature 392:25-30, the entire disclosures of which are incorporated herein by reference.

Particularly suitable viral vectors are those derived from AV and AAV. A suitable AV vector for expressing the miR gene products, a method for constructing the recombinant AV vector, and a method for delivering the vector into target cells, are described in Xia et al. (2002), Nat. Biotech. 20:1006-1010, the entire disclosure of which is incorporated herein by reference. Suitable AAV vectors for expressing the miR gene products, methods for constructing the recombinant AAV vector, and methods for delivering the vectors into target cells are described in Samulski et al. (1987), J. Virol. 61:3096-3101; Fisher et al. (1996), J. Virol., 70:520-532; Samulski et al. (1989), J. Virol. 63:3822-3826; U.S. Pat. No. 5,252,479; U.S. Pat. No. 5,139,941; International Patent Application No. WO 94/13788; and International Patent Application No. WO 93/24641, the entire disclosures of which are incorporated herein by reference. In one embodiment, the miR gene products are expressed from a single recombinant AAV vector comprising the CMV intermediate early promoter.

In a certain embodiment, a recombinant AAV viral vector of the invention comprises a nucleic acid sequence encoding a miR precursor RNA in operable connection with a polyT termination sequence under the control of a human U6 RNA promoter. As used herein, “in operable connection with a polyT termination sequence” means that the nucleic acid sequences encoding the sense or antisense strands are immediately adjacent to the polyT termination signal in the 5′ direction. During transcription of the miR sequences from the vector, the polyT termination signals act to terminate transcription.

In other embodiments of the treatment methods of the invention, an effective amount of at least one compound which inhibits miR expression can also be administered to the subject. As used herein, “inhibiting miR expression” means that the production of the active, mature form of miR gene product after treatment is less than the amount produced prior to treatment. One skilled in the art can readily determine whether miR expression has been inhibited in a cancer cell, using for example the techniques for determining miR transcript level discussed above for the diagnostic method Inhibition can occur at the level of gene expression (such as, by inhibiting transcription of a miR gene encoding the miR gene product) or at the level of processing (such as, by inhibiting processing of a miR precursor into a mature, active miR).

As used herein, an “effective amount” of a compound that inhibits miR expression is an amount sufficient to inhibit proliferation of a cancer cell in a subject suffering from a cancer associated with a cancer-associated chromosomal feature. One skilled in the art can readily determine an effective amount of an miR expression-inhibiting compound to be administered to a given subject, by taking into account factors, such as the size and weight of the subject; the extent of disease penetration; the age, health and sex of the subject; the route of administration; and whether the administration is regional or systemic.

For example, an effective amount of the expression-inhibiting compound can be based on the approximate weight of a tumor mass to be treated. The approximate weight of a tumor mass can be determined by calculating the approximate volume of the mass, wherein one cubic centimeter of volume is roughly equivalent to one gram. An effective amount based on the weight of a tumor mass can be between about 10-500 micrograms/gram of tumor mass, at least about 10 micrograms/gram of tumor mass, at least about 60 micrograms/gram of tumor mass, and at least about 100 micrograms/gram of tumor mass.

An effective amount of a compound that inhibits miR expression can also be based on the approximate or estimated body weight of a subject to be treated. Such effective amounts are administered parenterally or enterally, among others, as described herein. For example, an effective amount of the expression-inhibiting compound administered to a subject can range from about 5-3000 micrograms/kg of body weight, from about 700-1000 micrograms/kg of body weight, or it can be greater than about 1000 micrograms/kg of body weight.

One skilled in the art can also readily determine an appropriate dosage regimen for administering a compound that inhibits miR expression to a given subject. For example, an expression-inhibiting compound can be administered to the subject once (for example, as a single injection or deposition). Alternatively, an expression-inhibiting compound can be administered once or twice daily to a subject for a period of from about three to about twenty-eight days, more preferably from about seven to about ten days. In a particular dosage regimen, an expression-inhibiting compound is administered once a day for seven days. Where a dosage regimen comprises multiple administrations, it is understood that the effective amount of the expression-inhibiting compound administered to the subject can comprise the total amount of compound administered over the entire dosage regimen.

Suitable compounds for inhibiting miR gene expression include double-stranded RNA (such as short- or small-interfering RNA or “siRNA”), antisense nucleic acids, and enzymatic RNA molecules, such as ribozymes. Each of these compounds can be targeted to a given miR gene product and destroy or induce the destruction of the target miR gene product.

For example, expression of a given miR gene can be inhibited by inducing RNA interference of the miR gene with an isolated double-stranded RNA (“dsRNA”) molecule which has at least 90%, for example at least 95%, at least 98%, at least 99% or 100%, sequence homology with at least a portion of the miR gene product. In a particular embodiment, the dsRNA molecule is a “short or small interfering RNA” or “siRNA.”

siRNA useful in the present methods comprise short double-stranded RNA from about 17 nucleotides to about 29 nucleotides in length, preferably from about 19 to about 25 nucleotides in length. The siRNA comprise a sense RNA strand and a complementary antisense RNA strand annealed together by standard Watson-Crick base-pairing interactions (hereinafter “base-paired”). The sense strand comprises a nucleic acid sequence which is substantially identical to a nucleic acid sequence contained within the target miR gene product.

As used herein, a nucleic acid sequence in a siRNA which is “substantially identical” to a target sequence contained within the target mRNA is a nucleic acid sequence that is identical to the target sequence, or that differs from the target sequence by one or two nucleotides. The sense and antisense strands of the siRNA can comprise two complementary, single-stranded RNA molecules, or can comprise a single molecule in which two complementary portions are base-paired and are covalently linked by a single-stranded “hairpin” area.

The siRNA can also be altered RNA that differs from naturally-occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of the siRNA or to one or more internal nucleotides of the siRNA, or modifications that make the siRNA resistant to nuclease digestion, or the substitution of one or more nucleotides in the siRNA with deoxyribonucleotides.

One or both strands of the siRNA can also comprise a 3′ overhang. As used herein, a “3′ overhang” refers to at least one unpaired nucleotide extending from the 3′-end of a duplexed RNA strand. Thus, in certain embodiments, the siRNA comprises at least one 3′ overhang of from 1 to about 6 nucleotides (which includes ribonucleotides or deoxyribonucleotides) in length, from 1 to about 5 nucleotides in length, from 1 to about 4 nucleotides in length, or from about 2 to about 4 nucleotides in length. In a particular embodiment, the 3′ overhang is present on both strands of the siRNA, and is 2 nucleotides in length. For example, each strand of the siRNA can comprise 3′ overhangs of dithymidylic acid (“TT”) or diuridylic acid (“uu”).

The siRNA can be produced chemically or biologically, or can be expressed from a recombinant plasmid or viral vector, as described above for the isolated miR gene products. Exemplary methods for producing and testing dsRNA or siRNA molecules are described in U.S. Published Patent Application No. 2002/0173478 to Gewirtz and in U.S. Pat. No. 7,148,342 to Reich et al., the entire disclosures of which are incorporated herein by reference.

Expression of a given miR gene can also be inhibited by an antisense nucleic acid. As used herein, an “antisense nucleic acid” refers to a nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-peptide nucleic acid interactions, which alters the activity of the target RNA. Antisense nucleic acids suitable for use in the present methods are single-stranded nucleic acids (for example, RNA, DNA, RNA-DNA chimeras, PNA) that generally comprise a nucleic acid sequence complementary to a contiguous nucleic acid sequence in an miR gene product. The antisense nucleic acid can comprise a nucleic acid sequence that is 50-100% complementary, 75-100% complementary, or 95-100% complementary to a contiguous nucleic acid sequence in an miR gene product. Nucleic acid sequences for the miR gene products are provided in Table 1. Without wishing to be bound by any theory, it is believed that the antisense nucleic acids activate RNase H or another cellular nuclease that digests the miR gene product/antisense nucleic acid duplex.

Antisense nucleic acids can also contain modifications to the nucleic acid backbone or to the sugar and base moieties (or their equivalent) to enhance target specificity, nuclease resistance, delivery or other properties related to efficacy of the molecule. Such modifications include cholesterol moieties, duplex intercalators, such as acridine, or one or more nuclease-resistant groups.

Antisense nucleic acids can be produced chemically or biologically, or can be expressed from a recombinant plasmid or viral vector, as described above for the isolated miR gene products. Exemplary methods for producing and testing are within the skill in the art; see, for example, Stein and Cheng (1993), Science 261:1004 and U.S. Pat. No. 5,849,902 to Woolf et al., the entire disclosures of which are incorporated herein by reference.

Expression of a given miR gene can also be inhibited by an enzymatic nucleic acid. As used herein, an “enzymatic nucleic acid” refers to a nucleic acid comprising a substrate binding region that has complementarity to a contiguous nucleic acid sequence of an miR gene product, and which is able to specifically cleave the miR gene product. The enzymatic nucleic acid substrate binding region can be, for example, 50-100% complementary, 75-100% complementary, or 95-100% complementary to a contiguous nucleic acid sequence in a miR gene product. The enzymatic nucleic acids can also comprise modifications at the base, sugar, and/or phosphate groups. An exemplary enzymatic nucleic acid for use in the present methods is a ribozyme.

The enzymatic nucleic acids can be produced chemically or biologically, or can be expressed from a recombinant plasmid or viral vector, as described above for the isolated miR gene products. Exemplary methods for producing and testing dsRNA or siRNA molecules are described in Werner and Uhlenbeck (1995), Nucl. Acids Res. 23:2092-96; Hammann et al. (1999), Antisense and Nucleic Acid Drug Dev. 9:25-31; and U.S. Pat. No. 4,987,071 to Cech et al, the entire disclosures of which are incorporated herein by reference.

Administration of at least one miR gene product, or at least one compound for inhibiting miR expression, will inhibit the proliferation of cancer cells in a subject who has a cancer associated with a cancer-associated chromosomal feature. As used herein, to “inhibit the proliferation of a cancer cell” means to kill the cell, or permanently or temporarily arrest or slow the growth of the cell. Inhibition of cancer cell proliferation can be inferred if the number of such cells in the subject remains constant or decreases after administration of the miR gene products or miR gene expression-inhibiting compounds. An inhibition of cancer cell proliferation can also be inferred if the absolute number of such cells increases, but the rate of tumor growth decreases.

The number of cancer cells in a subject's body can be determined by direct measurement, or by estimation from the size of primary or metastatic tumor masses. For example, the number of cancer cells in a subject can be measured by immunohistological methods, flow cytometry, or other techniques designed to detect characteristic surface markers of cancer cells.

The size of a tumor mass can be ascertained by direct visual observation, or by diagnostic imaging methods, such as X-ray, magnetic resonance imaging, ultrasound, and scintigraphy. Diagnostic imaging methods used to ascertain size of the tumor mass can be employed with or without contrast agents, as is known in the art. The size of a tumor mass can also be ascertained by physical means, such as palpation of the tissue mass or measurement of the tissue mass with a measuring instrument, such as a caliper.

The miR gene products or miR gene expression-inhibiting compounds can be administered to a subject by any means suitable for delivering these compounds to cancer cells of the subject. For example, the miR gene products or miR expression inhibiting compounds can be administered by methods suitable to transfect cells of the subject with these compounds, or with nucleic acids comprising sequences encoding these compounds. In one embodiment, the cells are transfected with a plasmid or viral vector comprising sequences encoding at least one miR gene product or miR gene expression inhibiting compound.

Transfection methods for eukaryotic cells are well known in the art, and include, for example, direct injection of the nucleic acid into the nucleus or pronucleus of a cell; electroporation; liposome transfer or transfer mediated by lipophilic materials; receptor-mediated nucleic acid delivery, bioballistic or particle acceleration; calcium phosphate precipitation, and transfection mediated by viral vectors.

For example, cells can be transfected with a liposomal transfer compound, such as, DOTAP (N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethyl-ammonium methylsulfate, Boehringer-Mannheim) or an equivalent, such as LIPOFECTIN. The amount of nucleic acid used is not critical to the practice of the invention; acceptable results may be achieved with 0.1-100 micrograms of nucleic acid/10⁵ cells. For example, a ratio of about 0.5 micrograms of plasmid vector in 3 micrograms of DOTAP per 10⁵ cells can be used.

A miR gene product or miR gene expression inhibiting compound can also be administered to a subject by any suitable enteral or parenteral administration route. Suitable enteral administration routes for the present methods include, for example, oral, rectal, or intranasal delivery. Suitable parenteral administration routes include, for example, intravascular administration (for example, intravenous bolus injection, intravenous infusion, intra-arterial bolus injection, intra-arterial infusion and catheter instillation into the vasculature); pen- and intra-tissue injection (for example, peri-tumoral and intra-tumoral injection, intra-retinal injection, or subretinal injection); subcutaneous injection or deposition, including subcutaneous infusion (such as by osmotic pumps); direct application to the tissue of interest, for example by a catheter or other placement device (for example, a retinal pellet or a suppository or an implant comprising a porous, non-porous, or gelatinous material); and inhalation. Particularly suitable administration routes are injection, infusion and direct injection into the tumor.

In the present methods, a miR gene product or miR gene product expression inhibiting compound can be administered to the subject either as naked RNA, in combination with a delivery reagent, or as a nucleic acid (for example, a recombinant plasmid or viral vector) comprising sequences that express the miR gene product or expression inhibiting compound. Suitable delivery reagents include, for example, the Mirus Transit TKO lipophilic reagent; lipofectin; lipofectamine; cellfectin; polycations (for example, polylysine), and liposomes.

Recombinant plasmids and viral vectors comprising sequences that express the miR gene products or miR gene expression inhibiting compounds, and techniques for delivering such plasmids and vectors to cancer cells, are discussed herein.

In a particular embodiment, liposomes are used to deliver a miR gene product or miR gene expression-inhibiting compound (or nucleic acids comprising sequences encoding them) to a subject. Liposomes can also increase the blood half-life of the gene products or nucleic acids. Suitable liposomes for use in the invention can be formed from standard vesicle-forming lipids, which generally include neutral or negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally guided by consideration of factors, such as the desired liposome size and half-life of the liposomes in the blood stream. A variety of methods are known for preparing liposomes, for example, as described in Szoka et al. (1980), Ann. Rev. Biophys. Bioeng. 9:467; and U.S. Pat. Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, the entire disclosures of which are incorporated herein by reference.

The liposomes for use in the present methods can comprise a ligand molecule that targets the liposome to cancer cells. Ligands which bind to receptors prevalent in cancer cells, such as monoclonal antibodies that bind to tumor cell antigens, are preferred.

The liposomes for use in the present methods can also be modified so as to avoid clearance by the mononuclear macrophage system (“MMS”) and reticuloendothelial system (“RES”). Such modified liposomes have opsonization-inhibition moieties on the surface or incorporated into the liposome structure. In a particularly preferred embodiment, a liposome of the invention can comprise both opsonization-inhibition moieties and a ligand.

Opsonization-inhibiting moieties for use in preparing the liposomes of the invention are typically large hydrophilic polymers that are bound to the liposome membrane. As used herein, an opsonization inhibiting moiety is “bound” to a liposome membrane when it is chemically or physically attached to the membrane, for example, by the intercalation of a lipid-soluble anchor into the membrane itself, or by binding directly to active groups of membrane lipids. These opsonization-inhibiting hydrophilic polymers form a protective surface layer that significantly decreases the uptake of the liposomes by the MMS and RES; for example, as described in U.S. Pat. No. 4,920,016, the entire disclosure of which is incorporated herein by reference.

Opsonization inhibiting moieties suitable for modifying liposomes are preferably water-soluble polymers with a number-average molecular weight from about 500 to about 40,000 daltons, and more preferably from about 2,000 to about 20,000 daltons. Such polymers include polyethylene glycol (PEG) or polypropylene glycol (PPG) derivatives; for example, methoxy PEG or PPG, and PEG or PPG stearate; synthetic polymers, such as polyacrylamide or poly N-vinyl pyrrolidone; linear, branched, or dendrimeric polyamidoamines; polyacrylic acids; polyalcohols, for example, polyvinylalcohol and polyxylitol to which carboxylic or amino groups are chemically linked, as well as gangliosides, such as ganglioside GM1. Copolymers of PEG, methoxy PEG, or methoxy PPG, or derivatives thereof, are also suitable. In addition, the opsonization inhibiting polymer can be a block copolymer of PEG and either a polyamino acid, polysaccharide, polyamidoamine, polyethyleneamine, or polynucleotide. The opsonization inhibiting polymers can also be natural polysaccharides containing amino acids or carboxylic acids, for example, galacturonic acid, glucuronic acid, mannuronic acid, hyaluronic acid, pectic acid, neuraminic acid, alginic acid, carrageenan; aminated polysaccharides or oligosaccharides (linear or branched); or carboxylated polysaccharides or oligosaccharides, for example, reacted with derivatives of carbonic acids with resultant linking of carboxylic groups. Preferably, the opsonization-inhibiting moiety is a PEG, PPG, or derivatives thereof. Liposomes modified with PEG or PEG-derivatives are sometimes called “PEGylated liposomes.”

The opsonization inhibiting moiety can be bound to the liposome membrane by any one of numerous well-known techniques. For example, an N-hydroxysuccinimide ester of PEG can be bound to a phosphatidyl-ethanolamine lipid-soluble anchor, and then bound to a membrane. Similarly, a dextran polymer can be derivatized with a stearylamine lipid-soluble anchor via reductive amination using Na(CN)BH₃ and a solvent mixture, such as tetrahydrofuran and water in a 30:12 ratio at 60° C.

Liposomes modified with opsonization-inhibition moieties remain in the circulation much longer than unmodified liposomes. For this reason, such liposomes are sometimes called “stealth” liposomes. Stealth liposomes are known to accumulate in tissues fed by porous or “leaky” microvasculature. Thus, tissue characterized by such microvasculature defects, for example solid tumors, will efficiently accumulate these liposomes; see Gabizon, et al. (1988), Proc. Natl. Acad. Sci., U.S.A., 18:6949-53. In addition, the reduced uptake by the RES lowers the toxicity of stealth liposomes by preventing significant accumulation of the liposomes in the liver and spleen. Thus, liposomes that are modified with opsonization-inhibition moieties are particularly suited to deliver the miR gene products or miR gene expression inhibition compounds (or nucleic acids comprising sequences encoding them) to tumor cells.

The miR gene products or miR gene expression inhibition compounds can be formulated as pharmaceutical compositions, sometimes called “medicaments,” prior to administering them to a subject, according to techniques known in the art. Accordingly, the invention encompasses pharmaceutical compositions for treating breast cancer. In one embodiment, the pharmaceutical compositions comprise at least one isolated miR gene product and a pharmaceutically-acceptable carrier. In a particular embodiment, the at least one miR gene product corresponds to a miR gene product that has a decreased level of expression in breast cancer cells relative to suitable control cells. In certain embodiments the isolated miR gene product is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In other embodiments, the pharmaceutical compositions of the invention comprise at least one miR expression inhibition compound. In a particular embodiment, the at least one miR gene expression inhibition compound is specific for a miR gene whose expression is greater in breast cancer cells than control cells. In certain embodiments, the miR gene expression inhibition compound is specific for one or more miR gene products selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

Pharmaceutical compositions of the present invention are characterized as being at least sterile and pyrogen-free. As used herein, “pharmaceutical formulations” include formulations for human and veterinary use. Methods for preparing pharmaceutical compositions of the invention are within the skill in the art, for example as described in Remington's Pharmaceutical Science, 17th ed., Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated herein by reference.

The present pharmaceutical formulations comprise at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) (for example, 0.1 to 90% by weight), or a physiologically acceptable salt thereof, mixed with a pharmaceutically-acceptable carrier. The pharmaceutical formulations of the invention can also comprise at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) which are encapsulated by liposomes and a pharmaceutically-acceptable carrier. In one embodiment, the pharmaceutical compositions comprise a miR gene or gene product that is not miR-15, miR-16, miR-143 and/or miR-145.

Especially suitable pharmaceutically-acceptable carriers are water, buffered water, normal saline, 0.4% saline, 0.3% glycine, hyaluronic acid and the like.

In a particular embodiment, the pharmaceutical compositions of the invention comprise at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) which is resistant to degradation by nucleases. One skilled in the art can readily synthesize nucleic acids which are nuclease resistant, for example by incorporating one or more ribonucleotides that are modified at the 2′-position into the miR gene products. Suitable 2′-modified ribonucleotides include those modified at the 2′-position with fluoro, amino, alkyl, alkoxy, and O-allyl.

Pharmaceutical compositions of the invention can also comprise conventional pharmaceutical excipients and/or additives. Suitable pharmaceutical excipients include stabilizers, antioxidants, osmolality adjusting agents, buffers, and pH adjusting agents. Suitable additives include, for example, physiologically biocompatible buffers (for example, tromethamine hydrochloride), additions of chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (such as, for example, calcium DTPA, CaNaDTPA-bisamide), or, optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate). Pharmaceutical compositions of the invention can be packaged for use in liquid form, or can be lyophilized.

For solid pharmaceutical compositions of the invention, conventional nontoxic solid pharmaceutically-acceptable carriers can be used; for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.

For example, a solid pharmaceutical composition for oral administration can comprise any of the carriers and excipients listed above and 10-95%, preferably 25%-75%, of the at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them). A pharmaceutical composition for aerosol (inhalational) administration can comprise 0.01-20% by weight, preferably 1%-10% by weight, of the at least one miR gene product or miR gene expression inhibition compound (or at least one nucleic acid comprising sequences encoding them) encapsulated in a liposome as described above, and a propellant. A carrier can also be included as desired; for example, lecithin for intranasal delivery.

The invention also encompasses methods of identifying an anti-breast cancer agent, comprising providing a test agent to a cell and measuring the level of at least one miR gene product in the cell. In one embodiment, the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with decreased expression levels in breast cancer cells. An increase in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, at least one miR gene product associated with decreased expression levels in breast cancer cells is selected from the group consisting of miR-145, miR-10b, miR-123 (miR-126), miR-140-as, miR-125a, miR-125b-1, miR-125b-2, miR-194, miR-204, let-7a-2, let-7a-3, let-7d (let-7d-v1), let-7f-2, miR-101-1, miR-143 and combinations thereof.

In other embodiments the method comprises providing a test agent to a cell and measuring the level of at least one miR gene product associated with increased expression levels in breast cancer cells. A decrease in the level of the miR gene product in the cell, relative to a suitable control cell, is indicative of the test agent being an anti-breast cancer agent. In a particular embodiment, at least one miR gene product associated with increased expression levels in breast cancer cells is selected from the group consisting of miR-21, miR-155, miR-009-1 (miR131-1), miR-34 (miR-170), miR-102 (miR-29b), miR-213, let-7i (let-7d-v2), miR-122a, miR-128b, miR-136, miR-149, miR-191, miR-196-1, miR-196-2, miR-202, miR-203, miR-206, miR-210, miR-213 and combinations thereof.

Suitable agents include, but are not limited to drugs (for example, small molecules, peptides), and biological macromolecules (for example, proteins, nucleic acids). The agent can be produced recombinantly, synthetically, or it may be isolated (i.e., purified) from a natural source. Various methods for providing such agents to a cell (for example, transfection) are well known in the art, and several of such methods are described hereinabove. Methods for detecting the expression of at least one miR gene product (for example, Northern blotting, in situ hybridization, RT-PCR, expression profiling) are also well known in the art. Several of these methods are also described hereinabove.

The invention will now be illustrated by the following non-limiting examples.

Example 1

Identification of a microRNA Expression Signature that Discriminates Breast Cancer Tissues from Normal Tissues

Materials and Methods

Breast Cancer Samples and Cell Lines.

RNAs from primary tumors were obtained from 76 samples collected at the University of Ferrara (Italy), Istituto Nazionale dei Tumori, Milano (Italy) and Thomas Jefferson University (Philadelphia, Pa.). Clinico-pathological information was available for 58 tumor samples. RNA from normal samples consisted of 6 pools of RNA from 5 normal breast tissues each, as well as RNA from 4 additional single breast tissues. Breast cancer RNAs were also obtained from the following cell lines: Hs578-T, MCF7, T47D, BT20, SK-BR-3, HBL100, HCC2218, MDA-MB-175, MDA-MB-231, MDA-MB-361, MDA-MB-435, MDA-MB-436, MDA-MB-453 and MDAMB-468.

miRNA Microarray.

Total RNA isolation was performed with Trizol Reagent (Invitrogen) according to the manufacturer's instructions. RNA labeling and hybridization on microRNA microarray chips was performed as previously described (Liu, C.-G., et al., Proc. Natl. Acad. Sci. U.S.A. 101:9740-9744 (2004)). Briefly, 5 μg of RNA from each sample was labeled with biotin during reverse transcription using random hexamers. Hybridization was carried out on a miRNA microarray chip (KCl version 1.0), which contains 368 probes, including 245 human and mouse miRNA genes, in triplicate. Hybridization signals were detected by binding of biotin to a Streptavidin-Alexa647 conjugate using a Perkin-Elmer ScanArray XL5K. Scanner images were quantified by the Quantarray software (Perkin Elmer).

Statistical and bioinformatic analysis of microarray data. Raw data were normalized and analyzed using the GeneSpring® software, version 7.2 (SiliconGenetics, Redwood City, Calif.). Expression data were median centered. Statistical comparisons were performed by ANOVA (Analysis of Variance), using the Benjamini and Hochberg correction for reduction of false positives. Prognostic miRNAs for tumor or normal class prediction were determined using both the PAM software (Prediction Analysis of Microarrays) (Tibshirani, R., et al. Proc. Natl. Acad. Sci. U.S.A. 99:6567-6572 (2002)) and the Support Vector Machine (Furey, T. S., et al. Bioinformatics 16: 906-914 (2000)) software. Both algorithms were used for Cross-validation and Test-set prediction. All data were submitted using MIAMExpress to the Array Express database.

Northern Blotting.

Northern blot analysis was performed as previously described (Calin, G. A., et al., Proc. Natl. Acad. Sci. U.S.A. 99:15524-29 (2002)). RNA samples (10 μg each) were electrophoresed on 15% acrylamide, 7 M urea Criterion pre-casted gels (Bio-Rad) and transferred onto Hybond-N+ membrane (Amersham Pharmacia Biotech). The hybridization was performed at 37° C. in 7% sodium dodecyl sulfate (SDS)/0.2M Na₂PO₄ (pH 7.0) for 16 hours. Membranes were washed twice at 42° C. with 2× standard saline phosphate (0.18 M NaCl/10 mM phosphate, pH 7.4), supplemented with 1 mM EDTA (SSPE) and 0.1% SDS, and twice with 0.5×SSPE/0.1% SDS. Oligonucleotide probes were complementary to the sequence of the corresponding mature microRNA (see Sanger miR Registry): miR-21 5′-TCA ACA TCA GTC TGA TAA GCT A-3′ (SEQ ID NO:287); miR-125b1: 5′-TCA CAA GTT AGG GTC TCA GGG A-3′ (SEQ ID NO:288); miR-145: 5′-AAG GGA TTC CTG GGA AAA CTG GAC-3′ (SEQ ID NO:289). An oligonucleotide that was complementary to the U6 RNA (5′-GCA GGG GCC ATG CTA ATC TTC TCT GTA TCG-3′ (SEQ ID NO:290)) was used for normalizing expression levels. 200 ng of each probe was end labeled with 100 mCi [gamma-³²P]-ATP using a polynucleotide kinase (Roche). Northern Blots were stripped in a boiling 0.1% SDS solution for 10 minutes before re-hybridization.

Results

A microRNA microarray (Liu, C.-G., et al., Proc. Natl. Acad. Sci. U.S.A. 101:9740-9744 (2004)) was used to generate microRNA expression profiles for 10 normal and 76 neoplastic breast tissues. Each tumor sample was derived from a single specimen, while 6 of the 10 normal samples consisted of pools of RNA made from five different normal breast tissues. Hence, 34 normal breast samples were actually examined in the study.

To identify miRNAs that were differentially-expressed between normal and tumor samples, and, therefore, can be used to distinguish normal from cancerous breast tissues, analyses of variance and class prediction statistical tools were utilized. Results of the ANOVA analysis on normalized data generated a profile of differentially-expressed miRNAs (p<0.05) between normal and cancerous breast tissues (Table 2). Cluster analysis, based on differentially-expressed miRNA, generated a tree having a clear distinction between normal and cancer tissues (FIG. 1A).

To accurately identify a set of predictive miRNAs capable of differentiating normal from breast cancer tissues, we used Support Vector Machine (GeneSpring software) and PAM (Prediction Analysis of Microarrays). Results from the two class prediction analyses largely overlapped (Table 3 and FIG. 1B). Among the miRNAs listed in Table 3, 11 of 15 have an ANOVA p-value of less than 0.05. To confirm the results obtained by microarray analysis, we performed Northern blot analysis to assess expression levels for a subset of microRNAs, namely, mir-125b, mir-145 and mir-21, that were differentially-expressed in normal and cancerous breast tissues. Northern blot analysis confirmed results obtained by microarray analysis. In many cases, expression differences appeared stronger than those anticipated by the microarray studies (FIG. 1C).

TABLE 2
miRNAs differentially-expressed between breast carcinoma and normal breast tissue.

Breast Cancer

Normal Breast

Median

Range

Median

Range

	P-value	Normalized	Min		Max	Normalized	Min		Max

let-7a-2	1.94E−02	1.67	0.96	-	6.21	2.30	1.34	-	5.00
let-7a-3	4.19E−02	1.28	0.81	-	3.79	1.58	1.02	-	2.91
let-7d (= 7d-v1)	4.81E−03	0.90	0.59	-	1.54	1.01	0.83	-	1.25
let-7f-2	6.57E−03	0.84	0.61	-	1.58	0.92	0.76	-	1.03
let-7f (= let-7d-v2)	3.38E−02	2.05	1.02	-	7.49	1.53	1.01	-	3.47
mir-009-1 (mir-131-1)	9.12E−03	1.38	0.69	-	4.18	1.01	0.81	-	2.44
mir-010b	4.49E−02	1.11	0.69	-	4.78	1.70	0.96	-	8.32
mir-021	4.67E−03	1.67	0.66	-	28.43	1.08	0.80	-	2.31
mir-034 (=mir-17D)	1.06E−02	1.87	0.70	-	8.40	1.09	0.65	-	3.17
mir-101-1	4.15E−03	0.83	0.52	-	1.28	0.90	0.77	-	1.05
mir-122a	3.43E−03	2.21	0.93	-	8.08	1.48	1.06	-	3.67
mir-125a	3.28E−03	1.20	0.69	-	2.35	1.73	1.21	-	3.34
mir-125b-1	2.85E−02	1.30	0.55	-	8.85	2.87	1.45	-	18.38
mir-125b-2	2.33E−02	1.26	0.69	-	8.29	2.83	1.40	-	18.78
mir-126b	1.60E−02	1.12	0.68	-	7.34	1.02	0.89	-	1.27
mir-136	2.42E−03	1.32	0.74	-	10.28	1.06	0.76	-	1.47
mir-143	7.11E−03	0.87	0.68	-	1.33	0.98	0.81	-	1.17
mir-145	4.02E−03	1.52	0.92	-	8.46	3.61	1.65	-	14.45
mir-149	2.75E−02	1.11	0.53	-	1.73	1.03	0.83	-	1.22
mir-155(BIC)	1.24E−03	1.75	0.95	-	11.45	1.37	1.11	-	1.88
mir-191	4.28E−02	5.17	1.03	-	37.81	3.12	1.45	-	14.58
mir-196-1	1.07E−02	1.20	0.57	-	3.95	0.95	0.66	-	1.75
mir-196-2	1.16E−03	1.46	0.57	-	5.55	1.04	0.79	-	1.80
mir-202	1.25E−02	1.05	0.71	-	2.03	0.89	0.65	-	1.20
mir-203	4.08E−07	1.12	0.50	-	5.89	0.86	0.71	-	1.04
mir-204	2.15E−03	0.78	0.48	-	1.04	0.89	0.72	-	1.08
mir-206	1.42E−02	2.55	1.22	-	8.42	1.95	1.34	-	3.22
mir-210	6.40E−13	1.60	0.98	-	12.13	1.12	0.97	-	1.29
mir-213	1.08E−02	3.72	1.42	-	40.83	2.47	1.35	-	5.91

TABLE 3
Normal and tumor breast tissues class predictor microRNAs

Median expression

ANOVAa

SVM prediction

PAM scorec

miRNA name	Cancer	Normal	Probability	strengthb	Cancer	Normal	Chromos map

mir-009-1	1.36	1.01	0.0091	8.05	0.011	−0.102	1q22
mir-010b	1.11	1.70	0.0449	8.70	−0.032	0.299	2q31
mir-021	1.67	1.08	0.0047	10.20	0.025	−0.235	17q23.2
mir-034	1.67	1.09	0.0108	8.05	0.011	−0.106	1p36.22
mir-102 (mir-29b)	1.36	1.14	>0.10	8.92	0.000	−0.004	1q32.2-32.3
mir-123 (mir-126)	0.92	1.13	0.0940	9.13	−0.015	0.138	9q34
mir-125a	1.20	1.73	0.0033	8.99	−0.040	0.381	19q13.4
mir-125b-1	1.30	2.87	0.0265	14.78	−0.096	0.915	11q24.1
mir-125b-2	1.26	2.63	0.0233	17.62	−0.106	1.006	21q11.2
mir-140-as	0.93	1.10	0.0695	11.01	−0.005	0.050	16q22.1
mir-145	1.52	3.61	0.0040	12.93	−0.158	1.502	5q32-33
mir-155(BIC)	1.75	1.37	0.0012	10.92	0.003	−0.030	21q21
mir-194	0.96	1.09	>0.10	11.12	−0.025	0.234	1q41
mir-204	0.78	0.89	0.0022	8.10	−0.015	0.144	9q21.1
mir-213	3.72	2.47	0.0108	9.44	0.023	−0.220	1q31.3-q32.1
aAnalysis of Variance (Welch t-test in Genespring software package) as calculated in Table 2.
bSupport Vector Machine prediction analysis tool (from Genespring 7.2 software package).

Prediction strengths are calculated as negative natural log of the probability to predict the observed number of samples, in one of the two classes, by chance. The higher is the score, the best is the prediction strength.
c—Centroid scores for the two classes of the Prediction Analysis of Microarrays (Tibshirani, R., et al. Proc. Natl. Acad. Sci. U.S.A. 99:6567-6572 (2002)).

Of the 29 miRNAs whose expression is significantly (p<0.05) deregulated according to the microarray analysis, a set of 15 miRNAs were able to correctly predict the nature of the sample analyzed (i.e., normal vs. tumor) with 100% accuracy. Among the differentially-expressed miRNAs, miR-10b, miR-125b, miR145, miR-21 and miR-155 were the most consistently deregulated miRNAs in breast cancer samples. Three of these, namely, miR-10b, miR-125b and miR-145, were down-regulated, while the remaining two, miR-21 and miR-155, were up-regulated, suggesting that they might act as tumor suppressor genes or oncogenes, respectively.

Example 2

Determination of Putative Gene Targets of miRNAs that are Deregulated in Breast Cancer Tissues

At present, the lack of knowledge about bona fide miRNA gene targets hampers a full understanding of which biological functions are deregulated in cancers characterized by aberrant miRNA expression. To identify putative targets of the most significantly de-regulated miRNAs from our study: miR-10b, miR125b, miR-145, miR-21 and miR-155 (see Example 1), we utilized multiple computational approaches. In particular, the analysis was performed using three algorithms, miRanda, TargetScan and PicTar, which are used to predict human miRNA gene targets (Enright, A. J., et al. Genome Biol. 5:R1 (2003); Lewis, B. P. et al., Cell 115:787-798 (2003); Krek, A., et al., Nat. Genet. 37:495-500 (2005)). The results obtained using each of the three algorithms were cross-referenced with one another to validate putative targets, and only targets that were identified by at least 2 of the 3 algorithms were considered. Results of this analysis are presented in Table 4.

Several genes with potential oncogenic functions were identified as putative targets of miRNAs that are down-regulated in breast cancer samples. Notably, oncogenes were identified as targets of miR-10b (for example, FLT1, the v-crk homolog, the growth factor BDNF and the transducing factor SHC1), miR-125b (for example, YES, ETS1, TEL, AKT3, the growth factor receptor FGFR2 and members of the mitogen-activated signal transduction pathway VTS58635, MAP3K10, MAP3K11, MAPK14), and miR-145 (for example, MYCN, FOS, YES and FLI1, integration site of Friend leukemia virus, cell cycle promoters, such as cyclins D2 and L1, MAPK transduction proteins, such as MAP3K3 and MAP4K4). The proto-oncogene, YES, and the core-binding transcription factor, CBFB, were determined to be potential targets of both miR-125 and miR-145.

Consistent with these findings, multiple tumor suppressor genes were identified as targets of miR-21 and miR-155, miRNAs that are up-regulated in breast cancer cells. For miR-21, the TGFB gene was predicted as target by all three methods. For miR-155, potential targets included the tumor suppressor genes, SOCS1 and APC, and the kinase, WEE1, which blocks the activity of Cdc2 and prevents entry into mitosis. The hypoxia inducible factor, HIF1A, was also a predicted target of miR-155. Notably, the tripartite motif-containing protein TRIM2, the proto-oncogene, SKI, and the RAS homologs, RAB6A and RAB6C, were found as potential targets of both miR-21 and miR-155.

TABLE 4
Putative gene targets of differentially-expressed miRNA identified by at least two prediction methods

		Gene		Prediction
miRNA	Genbank	Symbol	Gene Name	algorithm	Gene Ontology condensed
miR-	AL117516	38596	strand-exchange protein 1	P + T	exonuclease activity|nucleus
10b
miR-	NM_004915	ABCG1	ATP-binding cassette,	P + T	ATP binding|ATPase activity|ATPase activity,
10b			sub-family G (WHITE),		coupled to transmembrane movement of
			member 1		substances|L-tryptophan transporter
					activity|cholesterol homeostasis|cholesterol
					metabolism|detection of hormone stimulus|integral to
					plasma membrane|lipid
					transport|membrane|membrane fraction|permease
					activity|protein dimerization activity|purine nucleotide
					transporter activity|response to organic substance
miR-	NM_001148	ANK2	ankyrin 2, neuronal	P + T	actin
10b					cytoskeleton|membrane|metabolism|oxidoreductase
					activity|protein binding|signal transduction|structural
					constituent of cytoskeleton
miR-	NM_020987	ANK3	ankyrin 3, node of	P + T	Golgi apparatus|cytoskeletal
10b			Ranvier (ankyrin G)		anchoring|cytoskeleton|cytoskeleton|endoplasmic
					reticulum|protein binding|protein targeting|signal
					transduction|structural constituent of cytoskeleton
miR-	NM_016376	ANKHZN	ANKHZN protein	P + T	endocytosis|endosome membrane|membrane|protein
10b					binding|zinc ion binding
miR-	NM_006380	APPBP2	amyloid beta precursor	P + T	binding|cytoplasm|intracellular protein
10b			protein (cytoplasmic		transport|membrane|microtubule associated
			tail) binding protein 2		complex|microtubule motor activity|nucleus
miR-	NM_006321	ARIH2	ariadne homolog 2	P + T	development|nucleic acid binding|nucleus|protein
10b			(Drosophila)		ubiquitination|ubiquitin ligase complex|ubiquitin-
					protein ligase activity|zinc ion binding
miR-	NM_001668	ARNT	aryl hydrocarbon	P + T	aryl hydrocarbon receptor nuclear translocator
10b			receptor nuclear		activity|nucleus|nucleus|protein-nucleus import,
			translocator		translocation|receptor activity|regulation of
					transcription, DNA-dependent|signal transducer
					activity|signal transduction|transcription coactivator
					activity|transcription factor activity|transcription
					factor activity
miR-	AI829840	ASXL1	ESTs, Weakly similar	P + T	nucleus|regulation of transcription, DNA-
10b			to SFRB_HUMAN		dependent|transcription
			Splicing factor
			arginine/serine-rich 11
			(Arginine-rich 54 kDa
			nuclear protein) (P54)
			[H. sapiens]
miR-	NM_021813	BACH2	BTB and CNC	P + T	DNA binding|nucleus|protein binding|regulation of
10b			homology 1, basic		transcription, DNA-dependent|transcription
			leucine zipper
			transcription factor 2
miR-	NM_013450	BAZ2B	bromodomain adjacent	P + T	DNA binding|nucleus|regulation of transcription,
10b			to zinc finger domain,		DNA-dependent|transcription
			2B
miR-	NM_001706	BCL6	B-cell CLL/lymphoma	P + T	inflammatory response|mediator complex|negative
10b			6 (zinc finger protein		regulation of transcription from RNA polymerase II
			51)		promoter|nucleus|positive regulation of cell
					proliferation|protein binding|regulation of
					transcription, DNA-
					dependent|transcription|transcription factor
					activity|zinc ion binding
miR-	NM_001709	BDNF	brain-derived	P + T	growth factor activity|growth factor
10b			neurotrophic factor		activity|neurogenesis
miR-	NM_006624	BS69	adenovirus 5 E1A	P + T	DNA binding|cell cycle|cell proliferation|negative
10b			binding protein		regulation of cell cycle|negative regulation of
					transcription from RNA polymerase II
					promoter|nucleus|regulation of transcription, DNA-
					dependent|transcription
miR-	AF101784	BTRC	beta-transducin repeat	P + T	Wnt receptor signaling pathway|endoplasmic
10b			containing		reticulum|ligase activity|signal transduction|ubiquitin
					conjugating enzyme activity|ubiquitin cycle|ubiquitin-
					dependent protein catabolism
miR-	NM_005808	C3orf8	HYA22 protein	P + T	biological_process unknown|molecular_function
10b					unknown|nucleus
miR-	BF111268	CAMK2G	calcium/calmodulin-	P + T	ATP binding|ATP binding|calcium- and calmodulin-
10b			dependent protein		dependent protein kinase activity|calcium-dependent
			kinase (CaM kinase) II		protein serine/threonine phosphatase
			gamma		activity|calmodulin binding|cellular_component
					unknown|insulin secretion|kinase activity|protein
					amino acid phosphorylation|protein amino acid
					phosphorylation|protein serine/threonine kinase
					activity|protein-tyrosine kinase activity|signal
					transduction|transferase activity
miR-	NM_020184	CNNM4	cyclin M4	P + T
10b
miR-	NM_022730	COPS7B	COP9 constitutive	P + T	signalosome complex
10b			photomorphogenic
			homolog subunit 7B
			(Arabidopsis)
miR-	NM_016823	CRK	v-crk sarcoma virus	P + T	SH3/SH2 adaptor activity|actin cytoskeleton
10b			CT10 oncogene		organization and biogenesis|cell
			homolog (avian)		motility|cytoplasm|intracellular signaling
					cascade|nucleus|regulation of transcription from RNA
					polymerase II promoter
miR-	NM_020248	CTNNBIP1	catenin, beta interacting	P + T	Wnt receptor signaling pathway|beta-catenin
10b			protein 1		binding|cell
					proliferation|development|nucleus|regulation of
					transcription, DNA-dependent|signal transduction
miR-	NM_018959	DAZAP1	DAZ associated protein 1	P + T	RNA binding|cell differentiation|nucleotide
10b					binding|nucleus|spermatogenesis
miR-	AL136828	DKFZP434K0427	hypothetical protein	P + T	cation transport|cation transporter activity
10b			DKFZp434K0427
miR-	R20763	DKFZp547J036	ELAV (embryonic	P + T
10b			lethal, abnormal vision,
			Drosophila)-like 3 (Hu
			antigen C)
miR-	AF009204	DLGAP2	discs, large	P + T	cell-cell signaling|membrane|nerve-nerve synaptic
10b			(Drosophila) homolog-		transmission|neurofilament|protein binding
			associated protein 2
miR-	NM_001949	E2F3	E2F transcription factor 3	P + T	nucleus|protein binding|regulation of cell
10b					cycle|regulation of transcription, DNA-
					dependent|transcription|transcription factor
					activity|transcription factor complex|transcription
					initiation from RNA polymerase II promoter
miR-	NM_022659	EBF2	early B-cell factor 2	P + T	DNA binding|development|nucleus|regulation of
10b					transcription, DNA-dependent|transcription
miR-	NM_004432	ELAVL2	ELAV (embryonic	P + T	RNA binding|mRNA 3′-UTR binding|nucleotide
10b			lethal, abnormal vision,		binding|regulation of transcription, DNA-dependent
			Drosophila)-like 2 (Hu
			antigen B)
miR-	NM_001420	ELAVL3	ELAV (embryonic	P + T	RNA binding|cell differentiation|mRNA 3′-UTR
10b			lethal, abnormal vision,		binding|neurogenesis|nucleotide binding
			Drosophila)-like 3 (Hu
			antigen C)
miR-	NM_004438	EPHA4	EphA4	P + T	ATP binding|ephrin receptor activity|integral to
10b					plasma membrane|membrane|protein amino acid
					phosphorylation|receptor activity|signal
					transduction|transferase activity|transmembrane
					receptor protein tyrosine kinase signaling pathway
miR-	AL035703	EPHA8;	EphA8	P + T
10b		EEK;
		HEK3;
		Hek3;
		KIAA1459
miR-	NM_004468	FHL3	four and a half LIM	P + T	muscle development|zinc ion binding
10b		domains 3
miR-	NM_024679	FLJ11939	hypothetical protein	P + T
10b			FLJ11939
miR-	AI742838	FLJ32122	hypothetical protein	P + T	GTP binding|GTPase binding|guanyl-nucleotide
10b			FLJ32122		exchange factor activity
miR-	AL040935	FLJ33957	hypothetical protein	P + T	protein binding
10b			FLJ33957
miR-	AA058828	FLT1	ESTs	P + T	ATP binding|angiogenesis|cell
10b					differentiation|extracellular space|integral to plasma
					membrane|membrane|positive regulation of cell
					proliferation|pregnancy|protein amino acid
					phosphorylation|receptor activity|transferase
					activity|transmembrane receptor protein tyrosine
					kinase signaling pathway|vascular endothelial growth
					factor receptor activity
miR-	NM_004860	FXR2	fragile X mental	P + T	RNA binding|cytoplasm|cytosolic large ribosomal
10b			retardation, autosomal		subunit (sensu Eukaryota)|nucleus
			homolog 2
miR-	NM_020474	GALNT1	UDP-N-acetyl-alpha-D-	P + T	Golgi apparatus|O-linked glycosylation|integral to
10b			galactosamine:polypeptide		membrane|manganese ion binding|polypeptide N-
			N-		acetylgalactosaminyltransferase activity|sugar
			acetylgalactosaminyl-		binding|transferase activity, transferring glycosyl
			transferase 1		groups
			(GalNAc-T1)
miR-	D87811	GATA6	GATA binding protein 6	P + T	muscle development|nucleus|positive regulation of
10b					transcription|regulation of transcription, DNA-
					dependent|transcription|transcription factor
					activity|transcriptional activator activity|zinc ion
					binding
miR-	NM_000840	GRM3	glutamate receptor,	P + T	G-protein coupled receptor protein signaling
10b			metabotropic 3		pathway|integral to plasma
					membrane|membrane|metabotropic glutamate,
					GABA-B-like receptor activity|negative regulation of
					adenylate cyclase activity|receptor activity|signal
					transduction|synaptic transmission
miR-	NM_005316	GTF2H1	general transcription	P + T	DNA repair|[RNA-polymerase]-subunit kinase
10b			factor IIH, polypeptide		activity|general RNA polymerase II transcription
			1, 62 kDa		factor activity|nucleus|regulation of cyclin dependent
					protein kinase activity|regulation of transcription,
					DNA-dependent|transcription|transcription factor
					TFIIH complex|transcription from RNA polymerase
					II promoter
miR-	AF232772	HAS3	hyaluronan synthase 3	P + T	carbohydrate metabolism|hyaluronan synthase
10b					activity|integral to plasma membrane|transferase
					activity, transferring glycosyl groups
miR-	AL023584	HIVEP2	human	P + T
10b			immunodeficiency virus
			type I enhancer binding
			protein 2
miR-	S79910	HOXA1	homeo box A1	P + T	RNA polymerase II transcription factor
10b					activity|development|nucleus|regulation of
					transcription, DNA-dependent|transcription factor
					activity
miR-	NM_030661	HOXA3	homeo box A3	P + T	development|nucleus|regulation of transcription,
10b					DNA-dependent|transcription factor activity
miR-	AW299531	HOXD10	homeo box D10	P + T	RNA polymerase II transcription factor
10b					activity|development|nucleus|regulation of
					transcription, DNA-dependent|transcription factor
					activity
miR-	BF031714	HYA22	HYA22 protein	P + T
10b
miR-	NM_001546	ID4	inhibitor of DNA	P + T	nucleus|regulation of transcription from RNA
10b			binding 4, dominant		polymerase II promoter|transcription corepressor
			negative helix-loop-		activity
			helix protein
miR-	NM_014333	IGSF4	immunoglobulin	P + T
10b			superfamily, member 4
miR-	NM_014271	IL1RAPL1	interleukin 1 receptor	P + T	integral to membrane|learning and/or
10b			accessory protein-like 1		memory|membrane|signal
					transduction|transmembrane receptor activity
miR-	D87450	KIAA0261	KIAA0261 protein	P + T
10b
miR-	AL117518	KIAA0978	KIAA0978 protein	P + T	nucleus|regulation of transcription, DNA-
10b					dependent|transcription
miR-	AK025960	KIAA1255	KIAA1255 protein	P + T	endocytosis|endosome membrane|membrane|protein
10b					binding|zinc ion binding
miR-	AB037797	KIAA1376	KIAA1376 protein	P + T
10b
miR-	NM_004795	KL	klotho	P + T	beta-glucosidase activity|carbohydrate
10b					metabolism|extracellular space|glucosidase
					activity|integral to membrane|integral to plasma
					membrane|membrane fraction|signal transducer
					activity|soluble fraction
miR-	NM_015995	KLF13	Kruppel-like factor 13	P + T	DNA binding|RNA polymerase II transcription factor
10b					activity|nucleus|regulation of transcription, DNA-
					dependent|transcription|transcription from RNA
					polymerase II promoter|zinc ion binding
miR-	NM_004235	KLF4	Kruppel-like factor 4	P + T	mesodermal cell fate determination|negative
10b			(gut)		regulation of cell proliferation|negative regulation of
					transcription, DNA-dependent|negative regulation of
					transcription, DNA-dependent|nucleic acid
					binding|nucleus|transcription|transcription factor
					activity|transcription factor activity|transcriptional
					activator activity|transcriptional activator
					activity|transcriptional repressor
					activity|transcriptional repressor activity|zinc ion
					binding|zinc ion binding
miR-	AW511293	LOC144455	hypothetical protein	P + T	regulation of cell cycle|regulation of transcription,
10b			BC016658		DNA-dependent|transcription factor
					activity|transcription factor complex
miR-	NM_014921	LPHN1	lectomedin-2	P + T	G-protein coupled receptor activity|integral to
10b					membrane|latrotoxin receptor
					activity|membrane|neuropeptide signaling
					pathway|receptor activity|signal transduction|sugar
					binding
miR-	NM_012325	MAPRE1	microtubule-associated	P + T	cell proliferation|cytokinesis|microtubule
10b			protein, RP/EB family,		binding|mitosis|protein C-terminus binding|regulation
			member 1		of cell cycle
miR-	AA824369	MGC4643	hypothetical protein	P + T	Wnt receptor signaling pathway|endoplasmic
10b			MGC4643		reticulum|ligase activity|signal transduction|ubiquitin
					conjugating enzyme activity|ubiquitin cycle|ubiquitin-
					dependent protein catabolism
miR-	NM_021090	MTMR3	myotubularin related	P + T	cytoplasm|hydrolase activity|inositol or
10b			protein 3		phosphatidylinositol phosphatase
					activity|membrane|membrane fraction|phospholipid
					dephosphorylation|protein amino acid
					dephosphorylation|protein serine/threonine
					phosphatase activity|protein tyrosine phosphatase
					activity|protein tyrosine/serine/threonine phosphatase
					activity|zinc ion binding
miR-	AI498126	NAC1	transcriptional repressor	P + T	protein binding
10b			NAC1
miR-	AF128458	NCOA6	nuclear receptor	P + T	DNA recombination|DNA repair|DNA
10b			coactivator 6		replication|brain development|chromatin
					binding|embryonic development (sensu
					Mammalia)|estrogen receptor binding|estrogen
					receptor signaling pathway|glucocorticoid receptor
					signaling pathway|heart development|ligand-
					dependent nuclear receptor transcription coactivator
					activity|myeloid blood cell
					differentiation|nucleus|nucleus|positive regulation of
					transcription from RNA polymerase II
					promoter|protein binding|regulation of transcription,
					DNA-dependent|response to hormone
					stimulus|retinoid X receptor binding|thyroid hormone
					receptor binding|transcription|transcription factor
					complex|transcription initiation from RNA
					polymerase II promoter|transcriptional activator
					activity
miR-	NM_006312	NCOR2	nuclear receptor co-	P + T	DNA binding|nucleus|regulation of transcription,
10b			repressor 2		DNA-dependent|transcription corepressor activity
miR-	NM_006599	NFAT5	nuclear factor of	P + T	RNA polymerase II transcription factor
10b			activated T-cells 5,		activity|excretion|nucleus|regulation of transcription,
			tonicity-responsive		DNA-dependent|signal transduction|transcription
					factor activity|transcription from RNA polymerase II
					promoter
miR-	NM_006981	NR4A3	nuclear receptor	M + P + T	binding|nucleus|nucleus|regulation of transcription,
10b			subfamily 4, group A,		DNA-dependent|steroid hormone receptor
			member 3		activity|steroid hormone receptor activity|thyroid
					hormone receptor activity|transcription|transcription
					factor activity
miR-	NM_003822	NR5A2	nuclear receptor	P + T	RNA polymerase II transcription factor activity,
10b			subfamily 5, group A,		enhancer
			member 2		binding|morphogenesis|nucleus|nucleus|regulation of
					transcription, DNA-dependent|steroid hormone
					receptor activity|transcription|transcription factor
					activity|transcription from RNA polymerase II
					promoter
miR-	AA295257	NRP2	neuropilin 2	P + T	angiogenesis|axon guidance|cell adhesion|cell
10b					adhesion|cell differentiation|electron transport|electron
					transporter activity|integral to membrane|integral to
					membrane|membrane|membrane
					fraction|neurogenesis|receptor activity|semaphorin
					receptor activity|vascular endothelial growth factor
					receptor activity|vascular endothelial growth factor
					receptor activity
miR-	NM_000430	PAFAH1B1	platelet-activating	P + T	astral microtubule|cell cortex|cell cycle|cell
10b			factor acetylhydrolase,		differentiation|cell
			isoform Ib, alpha		motility|cytokinesis|cytoskeleton|dynein
			subunit 45 kDa		binding|establishment of mitotic spindle
					orientation|kinetochore|lipid metabolism|microtubule
					associated complex|microtubule-based
					process|mitosis|neurogenesis|nuclear membrane|signal
					transduction
miR-	NM_013382	POMT2	putative protein O-	P + T	O-linked glycosylation|dolichyl-phosphate-mannose-
10b			mannosyltransferase		protein mannosyltransferase activity|endoplasmic
					reticulum|integral to membrane|magnesium ion
					binding|membrane|transferase activity, transferring
					glycosyl groups
miR-	BF337790	PURB	purine-rich element	P + T
10b			binding protein B
miR-	AI302106	RAP2A	RAP2A, member of	P + T	GTP binding|GTPase activity|membrane|signal
10b			RAS oncogene family		transduction|small GTPase mediated signal
					transduction
miR-	NM_002886	RAP2B	RAP2B, member of	P + T	GTP binding|protein transport|small GTPase mediated
10b			RAS oncogene family		signal transduction
miR-	NM_014781	RB1CC1	RB1-inducible coiled-	P + T	kinase activity
10b			coil 1
miR-	NM_012234	RYBP	RING1 and YY1	P + T	development|negative regulation of transcription from
10b			binding protein		RNA polymerase II promoter|nucleus|transcription
					corepressor activity
miR-	NM_005506	SCARB2	scavenger receptor class	P + T	cell adhesion|integral to plasma membrane|lysosomal
10b			B, member 2		membrane|membrane fraction|receptor activity
miR-	AF225986	SCN3A	sodium channel,	P + T	cation channel activity|cation transport|integral to
10b			voltage-gated, type III,		membrane|membrane|sodium ion transport|voltage-
			alpha polypeptide		gated sodium channel activity|voltage-gated sodium
					channel complex
miR-	NM_002997	SDC1	syndecan 1	P + T	cytoskeletal protein binding|integral to plasma
10b					membrane|membrane
miR-	NM_006924	SFRS1	splicing factor,	P + T	RNA binding|mRNA splice site selection|nuclear
10b			arginine/serine-rich 1		mRNA splicing, via spliceosome|nucleotide
			(splicing factor 2,		binding|nucleus
			alternate splicing factor)
miR-	AI809967	SHC1	SHC (Src homology 2	P + T	activation of MAPK|activation of MAPK|intracellular
10b			domain containing)		signaling cascade|phospholipid binding|phospholipid
			transforming protein 1		binding|plasma membrane|plasma membrane|positive
					regulation of cell proliferation|positive regulation of
					cell proliferation|positive regulation of
					mitosis|positive regulation of mitosis|regulation of cell
					growth|regulation of epidermal growth factor receptor
					activity|transmembrane receptor protein tyrosine
					kinase adaptor protein activity|transmembrane
					receptor protein tyrosine kinase adaptor protein
					activity
miR-	NM_018976	SLC38A	solute carrier family 38,	P + T	amino acid transport|amino acid-polyamine
10b			member 2		transporter activity|integral to
					membrane|membrane|oxygen transport|oxygen
					transporter activity|transport
miR-	NM_003794	SNX4	sorting nexin 4	P + T	endocytosis|intracellular signaling cascade|protein
10b					transport
miR-	NM_003103	SON	SON DNA binding	P + T	DNA binding|DNA binding|anti-apoptosis|double-
10b			protein		stranded RNA binding|intracellular|nucleic acid
					binding|nucleus
miR-	Z48199	syndecan-1		P + T
10b
miR-	NM_003222	TFAP2C	transcription factor AP-	P + T	cell-cell signaling|nucleus|regulation of transcription
10b			2 gamma (activating		from RNA polymerase II
			enhancer binding		promoter|transcription|transcription factor activity
			protein 2 gamma)
miR-	NM_003275	TMOD1	tropomodulin	P + T	actin binding|cytoskeleton|cytoskeleton organization
10b					and biogenesis|tropomyosin binding
miR-	NM_003367	USF2	upstream transcription	P + T	RNA polymerase II transcription factor
10b			factor 2, c-fos		activity|nucleus|regulation of transcription, DNA-
			interacting		dependent|transcription|transcription factor activity
miR-	N62196	ZNF367	zinc finger protein 367	P + T	nucleic acid binding|nucleus|zinc ion binding
10b
miR-	AI948503	ABCC4	ATP-binding cassette,	P + T	15-hydroxyprostaglandin dehydrogenase (NAD+)
125b			sub-family C		activity|ATP binding|ATPase activity|ATPase
			(CFTR/MRP), member 4		activity, coupled to transmembrane movement of
					substances|chloride channel activity|integral to
					membrane|ion transport|membrane
miR-	AL534702	ABHD3	abhydrolase domain	M + P + T
125b			containing 3
miR-	AL527773	ABR	active BCR-related	P + T	GTPase activator activity|guanyl-nucleotide exchange
125b			gene		factor activity|small GTPase mediated signal
					transduction
miR-	NM_020039	ACCN2	amiloride-sensitive	P + T	amiloride-sensitive sodium channel activity|integral to
125b			cation channel 2,		plasma membrane|ion channel activity|ion
			neuronal		transport|membrane|response to pH|signal
					transduction|sodium ion transport
miR-	NM_003816	ADAM9	a disintegrin and	P + T	SH3 domain binding|integral to plasma
125b			metalloproteinase		membrane|integrin binding|metalloendopeptidase
			domain 9 (meltrin		activity|protein binding|protein kinase binding|protein
			gamma)		kinase cascade|proteolysis and peptidolysis|zinc ion
					binding
miR-	L05500	ADCY1	adenylate cyclase 1	P + T	cAMP biosynthesis|calcium- and calmodulin-
125b			(brain)		responsive adenylate cyclase activity|calmodulin
					binding|integral to membrane|intracellular signaling
					cascade|magnesium ion binding
miR-	NM_017488	ADD2	adducin 2 (beta)	P + T	actin binding|actin cytoskeleton|calmodulin
125b					binding|membrane
miR-	NM_003488	AKAP1	A kinase (PRKA)	P + T	RNA binding|integral to
125b			anchor protein 1		membrane|mitochondrion|outer membrane
miR-	NM_005465	AKT3	v-akt murine thymoma	P + T	ATP binding|protein amino acid
125b			viral oncogene homolog		phosphorylation|protein serine/threonine kinase
			3 (protein kinase B,		activity|signal transduction|transferase activity
			gamma)
miR-	NM_001150	ANPEP	alanyl (membrane)	P + T	aminopeptidase activity|angiogenesis|cell
125b			aminopeptidase		differentiation|integral to plasma
			(aminopeptidase N,		membrane|membrane alanyl aminopeptidase
			aminopeptidase M,		activity|metallopeptidase activity|proteolysis and
			microsomal		peptidolysis|receptor activity|zinc ion binding
			aminopeptidase, CD13,
			p150)
miR-	AF193759	APBA2BP	amyloid beta (A4)	M + P + T	Golgi cis cisterna|Golgi cis cisterna|antibiotic
125b			precursor protein-		biosynthesis|calcium ion
			binding, family A,		binding|cytoplasm|cytoplasm|endoplasmic reticulum
			member 2 binding		membrane|endoplasmic reticulum
			protein		membrane|nucleus|oxidoreductase activity|protein
					binding|protein binding|protein binding|protein
					metabolism|protein metabolism|protein
					secretion|protein secretion|regulation of amyloid
					precursor protein biosynthesis
miR-	NM_000038	APC	adenomatosis polyposis	P + T	Wnt receptor signaling pathway|beta-catenin
125b			coli		binding|cell adhesion|microtubule binding|negative
					regulation of cell cycle|protein complex
					assembly|signal transduction
miR-	NM_001655	ARCN1	archain 1	P + T	COPI vesicle coat|Golgi apparatus|clathrin vesicle
125b					coat|intra-Golgi transport|intracellular protein
					transport|intracellular protein
					transport|membrane|retrograde transport, Golgi to
					ER|transport
miR-	BC001719	ASB6	ankyrin repeat and	M + P	intracellular signaling cascade
125b			SOCS box-containing 6
miR-	AI478147	ATP10D	ATPase, Class V, type	P + T	ATP binding|ATPase activity|cation
125b			10D		transport|hydrolase activity|integral to
					membrane|magnesium ion
					binding|membrane|phospholipid-translocating ATPase
					activity
miR-	NM_012069	ATP1B4	ATPase, (Na+)/K+	P + T	hydrogen ion transporter activity|integral to plasma
125b			transporting, beta 4		membrane|ion transport|membrane|potassium ion
			polypeptide		transport|proton transport|sodium ion
					transport|sodium:potassium-exchanging ATPase
					activity
miR-	NM_005176	ATP5G2	ATP synthase, H+	M + P + T	ATP synthesis coupled proton transport|hydrogen-
125b			transporting,		transporting ATP synthase activity, rotational
			mitochondrial F0		mechanism|hydrogen-transporting ATPase activity,
			complex, subunit c		rotational mechanismlion transport|lipid
			(subunit 9), isoform 2		binding|membrane|membrane
					fraction|mitochondrion|proton transport|proton-
					transporting ATP synthase complex (sensu
					Eukaryota)|proton-transporting two-sector ATPase
					complex|transporter activity
miR-	NM_001702	BAI1	brain-specific	M + P + T	G-protein coupled receptor
125b			angiogenesis inhibitor 1		activity|axonogenesis|brain-specific angiogenesis
					inhibitor activity|cell adhesion|integral to plasma
					membrane|intercellular junction|negative regulation of
					cell proliferation|neuropeptide signaling
					pathway|peripheral nervous system
					development|plasma membrane|protein
					binding|receptor activity|signal transduction
miR-	NM_001188	BAK1	BCL2-antagonist/killer 1	M + T	apoptotic mitochondrial changes|induction of
125b					apoptosis|integral to membrane|protein
					heterodimerization activity|regulation of apoptosis
miR-	NM_013449	BAZ2A	bromodomain adjacent	P + T	DNA binding|chromatin remodeling|nucleolus
125b			to zinc finger domain,		organizer complex|nucleus|regulation of transcription,
			2A		DNA-dependent|transcription|transcription regulator
					activity
miR-	NM_004634	BRPF1	bromodomain and PHD	M + P + T	DNA binding|nucleus|nucleus|regulation of
125b			finger containing, 1		transcription, DNA-dependent|transcription|zinc ion
					binding
miR-	NM_003458	BSN	bassoon (presynaptic	P + T	cytoskeleton|metal ion binding|nucleus|structural
125b			cytomatrix protein)		constituent of cytoskeleton|synapse|synaptic
					transmission|synaptosome
miR-	NM_018108	C14orf130	hypothetical protein	P + T	ubiquitin cycle|ubiquitin-protein ligase activity
125b			FLJ10483
miR-	AA025877	C20orf136	chromosome 20 open	P + T
125b			reading frame 136
miR-	AB054985	CACNB1	calcium channel,	M + P + T	calcium ion transport|ion transport|membrane
125b			voltage-dependent, beta		fraction|muscle contraction|voltage-gated calcium
			1 subunit		channel activity|voltage-gated calcium channel
					complex
miR-	NM_001224	CASP2	caspase 2, apoptosis-	P + T	anti-apoptosis|apoptotic program|caspase
125b			related cysteine		activity|caspase activity|caspase activity|cysteine-type
			protease (neural		peptidase activity|enzyme binding|intracellular|protein
			precursor cell		binding|proteolysis and peptidolysis|proteolysis and
			expressed,		peptidolysis|regulation of apoptosis
			developmentally down-
			regulated 2)
miR-	NM_001755	CBFB	core-binding factor,	M + P + T	RNA polymerase II transcription factor
125b			beta subunit		activity|nucleus|transcription coactivator
					activity|transcription factor activity|transcription from
					RNA polymerase II promoter
miR-	AV648364	CBX7	ESTs, Highly similar to	P + T	chromatin|chromatin assembly or
125b			potassium voltage-gated		disassembly|chromatin binding|chromatin
			channel, Isk-related		modification|nucleus|regulation of transcription,
			subfamily, gene 4;		DNA-dependent|transcription
			potassium voltage-gated
			channel-like protein,
			Isk-related subfamily
			[Homo sapiens]
			[H. sapiens]
miR-	NM_001408	CELSR2	cadherin, EGF LAG	M + P + T	G-protein coupled receptor activity|calcium ion
125b			seven-pass G-type		binding|cell adhesion|development|homophilic cell
			receptor 2 (flamingo		adhesion|integral to
			homolog, Drosophila)		membrane|membrane|neuropeptide signaling
					pathway|receptor activity|signal
					transduction|structural molecule activity
miR-	NM_015955	CGI-27	C21orf19-like protein	P + T
125b
miR-	AF263462	CGN	cingulin	P + T	actin binding|biological_process unknown|motor
125b					activity|myosin|protein binding|tight junction
miR-	AF064491	CLIM2	LIM domain binding 1	P + T	LIM domain
125b					binding|development|development|negative regulation
					of transcription, DNA-dependent|nucleus|transcription
					cofactor activity|transcriptional repressor activity
miR-	AU152178	CMG2	capillary	P + T	integral to membrane|receptor activity
125b			morphogenesis protein 2
miR-	NM_004073	CNK	cytokine-inducible	P + T	ATP binding|protein amino acid
125b			kinase		phosphorylation|protein binding|protein
					serine/threonine kinase activity|regulation of cell
					cycle|transferase activity
miR-	NM_020348	CNNM1	cyclin M1	M + P + T	fatty acid biosynthesis
125b
miR-	NM_022730	COPS7B	COP9 constitutive	M + P + T	signalosome complex
125b			photomorphogenic
			homolog subunit 7B
			(Arabidopsis)
miR-	NM_003389	CORO2A	coronin, actin binding	P + T	actin binding|glutamate-ammonia ligase
125b			protein, 2A		activity|glutamine biosynthesis|intracellular signaling
					cascade|nitrogen compound metabolism|protein
					binding
miR-	BF939649	CORO2B	coronin, actin binding	P + T	actin binding|actin cytoskeleton|actin cytoskeleton
125b			protein, 2B		organization and biogenesis|membrane
miR-	NM_007007	CPSF6	cleavage and	P + T	RNA binding|mRNA processing|nucleic acid
125b			polyadenylation		binding|nucleotide binding|nucleus
			specific factor 6, 68 kDa
miR-	NM_004386	CSPG3	chondroitin sulfate	P + T	calcium ion binding|cell adhesion|cell
125b			proteoglycan 3		motility|hyaluronic acid binding|sugar binding
			(neurocan)
miR-	NM_004393	DAG1	dystroglycan 1	M + P + T	actin cytoskeleton|calcium ion binding|extracellular
125b			(dystrophin-associated		matrix (sensu Metazoa)|integral to plasma
			glycoprotein 1)		membrane|laminin receptor activity|membrane
					fraction|muscle contraction|plasma membrane|protein
					binding|protein complex assembly
miR-	NM_014764	DAZAP2	DAZ associated protein 2	P + T
125b
miR-	NM_030927	DC-	tetraspanin similar to	P + T	integral to membrane
125b		TM4F2	TM4SF9
miR-	NM_004082	DCTN1	dynactin 1 (p150, glued	M + P + T	cytoplasm|cytoskeleton|dynein complex|mitosis|motor
125b			homolog, Drosophila)		activity|neurogenesis
miR-	NM_030621	DICER1	Dicer1, Dcr-1 homolog	P + T	ATP binding|ATP-dependent helicase activity|RNA
125b			(Drosophila)		interference, targeting of mRNA for destruction|RNA
					processing|double-stranded RNA
					binding|endonuclease activity|hydrolase
					activity|intracellular|ribonuclease III activity
miR-	U53506	DIO2	deiodinase,	P + T	integral to membrane|membrane|selenium
125b			iodothyronine, type II		binding|selenocysteine incorporation|thyroid hormone
					generation|thyroxine 5′-deiodinase activity|thyroxine
					5′-deiodinase activity
miR-	AL136139	dJ761I2.1		P + T
125b
miR-	AL357503	dJ899C14.1	Q9H4T4 like	P + T
125b
miR-	AL117482	DKFZP434C131	DKFZP434C131	P + T	ATP binding|protein amino acid
125b			protein		phosphorylation|protein serine/threonine kinase
					activity|protein-tyrosine kinase activity|transferase
					activity
miR-	AK023580	DKFZP434H0820	hypothetical protein	P + T
125b			DKFZp434H0820
miR-	T16388	DKFZp564A176	hypothetical protein	P + T	development|integral to membrane|membrane|receptor
125b			DKFZp564A176		activity|semaphorin receptor activity
miR-	AL137517	DKFZp564O1278	hypothetical protein	P + T	integral to membrane
125b			DKFZp564O1278
miR-	BE781961	DKFZp762A2013	hypothetical protein	P + T	electron transport|electron transporter activity
125b			DKFZp762A2013
miR-	AB036931	DLL4	delta-like 4	M + P + T	Notch binding|Notch signaling pathway|cell
125b			(Drosophila)		differentiation|circulation|integral to
					membrane|membrane|signal transduction
miR-	NM_012266	DNAJB5	DnaJ (Hsp40) homolog,	P + T	heat shock protein binding|protein folding|response to
125b			subfamily B, member 5		unfolded protein|unfolded protein binding
miR-	NM_005740	DNAL4	dynein, axonemal, light	P + T	ATPase activity, coupled|axonemal dynein
125b			polypeptide 4		complex|microtubule motor activity|microtubule-
					based movement
miR-	BF593175	DOCK3	dedicator of cyto-	P + T	GTP binding|GTPase binding|guanyl-nucleotide
125b			kinesis 3		exchange factor activity
miR-	NM_006426	DPYSL4	dihydropyrimidinase-	P + T	hydrolase activity|neurogenesis
125b			like 4
miR-	NM_006465	DRIL2	dead ringer	P + T	DNA binding|biological_process unknown|nucleus
125b			(Drosophila)-like 2
			(bright and dead ringer)
miR-	BC005047	DUSP6	dual specificity	P + T	MAP kinase phosphatase activity|cytoplasm|hydrolase
125b			phosphatase 6		activity|inactivation of MAPK|protein amino acid
					dephosphorylation|protein serine/threonine
					phosphatase activity|protein tyrosine phosphatase
					activity|regulation of cell cycle|soluble fraction
miR-	NM_004423	DVL3	dishevelled, dsh	P + T	development|frizzled signaling pathway|heart
125b			homolog 3 (Drosophila)		development|intracellular|intracellular signaling
					cascade|kinase activity|neurogenesis|protein
					binding|signal transducer activity
miR-	NM_001949	E2F3	E2F transcription factor 3	P + T	nucleus|protein binding|regulation of cell
125b					cycle|regulation of transcription, DNA-
					dependent|transcription|transcription factor
					activity|transcription factor complex|transcription
					initiation from RNA polymerase II promoter
miR-	AU149385	EAF1	Homo sapiens cDNA	P + T
125b			FLJ13155 fis, clone
			NT2RP3003433,
			mRNA sequence
miR-	NM_014674	EDEM	KIAA0212 gene	P + T	ER-associated protein catabolism|GTP binding|N-
125b			product		linked glycosylation|calcium ion binding|endoplasmic
					reticulum|integral to endoplasmic reticulum
					membrane|integral to membrane|mannosyl-
					oligosaccharide 1,2-alpha-mannosidase
					activity|membrane|protein binding|response to
					unfolded protein
miR-	NM_001955	EDN1	endothelin 1	M + P + T	cell-cell signaling|extracellular space|hormone
125b					activity|pathogenesis|positive regulation of cell
					proliferation|regulation of blood pressure|regulation of
					vasoconstriction|signal transduction|soluble fraction
miR-	AI832074	EIF2C2	eukaryotic translation	M + P	cellular_component unknown|protein
125b			initiation factor 2C, 2		biosynthesis|translation initiation factor activity
miR-	AB044548	EIF4EBP1	eukaryotic translation	P + T	eukaryotic initiation factor 4E binding|negative
125b			initiation factor 4E		regulation of protein biosynthesis|negative regulation
			binding protein 1		of translational initiation|regulation of translation
miR-	NM_020390	EIF5A2	eukaryotic translation	P + T	DNA binding|protein biosynthesis|translation
125b			initiation factor 5A2		initiation factor activity|translational initiation
miR-	NM_004438	EPHA4	EphA4	P + T	ATP binding|ephrin receptor activity|integral to
125b					plasma membrane|membrane|protein amino acid
					phosphorylation|receptor activity|signal
					transduction|transferase activity|transmembrane
					receptor protein tyrosine kinase signaling pathway
miR-	NM_004451	ESRRA	estrogen-related	P + T	nucleus|regulation of transcription, DNA-
125b			receptor alpha		dependent|steroid binding|steroid hormone receptor
					activity|transcription|transcription factor activity
miR-	NM_004907	ETR101	immediate early protein	P + T
125b
miR-	NM_005238	ETS1	v-ets erythroblastosis	P + T	RNA polymerase II transcription factor
125b			virus E26 oncogene		activity|immune response|negative regulation of cell
			homolog 1 (avian)		proliferation|nucleus|regulation of transcription,
					DNA-dependent|transcription|transcription factor
					activity|transcription from RNA polymerase II
					promoter
miR-	NM_001987	ETV6	ets variant gene 6 (TEL	P + T	nucleus|regulation of transcription, DNA-
125b			oncogene)		dependent|transcription|transcription factor activity
miR-	NM_022763	FAD104	FAD104	P + T
125b
miR-	AF308300	FAPP2	phosphoinositol 4-	P + T
125b			phosphate adaptor
			protein-2
miR-	NM_022976	FGFR2	fibroblast growth factor	M + P + T	ATP binding|cell growth|fibroblast growth factor
125b			receptor 2 (bacteria-		receptor activity|heparin binding|integral to
			expressed kinase,		membrane|membrane|protein amino acid
			keratinocyte growth		phosphorylation|protein amino acid
			factor receptor,		phosphorylation|protein serine/threonine kinase
			craniofacial dysostosis		activity|protein-tyrosine kinase activity|protein-
			1, Crouzon syndrome,		tyrosine kinase activity|receptor activity|transferase
			Pfeiffer syndrome,		activity
			Jackson-Weiss
			syndrome)
miR-	NM_004470	FKBP2	FK506 binding protein	P + T	FK506 binding|endoplasmic reticulum|isomerase
125b			2, 13 kDa		activity|peptidyl-prolyl cis-trans isomerase
					activity|protein folding
miR-	AL160175	FKHL18	forkhead-like 18	P + T
125b			(Drosophila)
miR-	BF515132	FLJ00024	hypothetical protein	P + T
125b			FLJ00024
miR-	BC002945	FLJ10101	hypothetical protein	M + P	GTP binding|protein transport|small GTPase mediated
125b			FLJ10101		signal transduction
miR-	NM_018243	FLJ10849	hypothetical protein	P + T	GTP binding|cell cycle|cytokinesis
125b			FLJ10849
miR-	NM_019084	FLJ10895	hypothetical protein	P + T	nucleus|regulation of cell cycle
125b			FLJ10895
miR-	NM_018320	FLJ11099	hypothetical protein	P + T	protein ubiquitination|ubiquitin ligase
125b			FLJ11099		complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	NM_018375	FLJ11274	hypothetical protein	M + P + T	membrane|metal ion transport|metal ion transporter
125b			FLJ11274		activity
miR-	NM_024954	FLJ11807	hypothetical protein	P + T	protein modification
125b			FLJ11807
miR-	BF434995	FLJ14708	hypothetical protein	P + T
125b			FLJ14708
miR-	NM_018992	FLJ20040	hypothetical protein	P + T	membrane|potassium ion transport|protein
125b			FLJ20040		binding|voltage-gated potassium channel
					activity|voltage-gated potassium channel complex
miR-	NM_017911	FLJ20635	hypothetical protein	P + T
125b			FLJ20635
miR-	NM_017936	FLJ2070	hypothetical protein	M + P + T	ATP synthesis coupled proton
125b			FLJ20707		transport|cytoplasm|hydrogen-transporting ATP
					synthase activity, rotational mechanism|hydrogen-
					transporting ATPase activity, rotational
					mechanism|membrane|phosphate transport|proton-
					transporting two-sector ATPase complex
miR-	NM_024789	FLJ22529	hypothetical protein	P + T
125b			FLJ22529
miR-	AA721230	FLJ25604	hypothetical protein	P + T	guanyl-nucleotide exchange factor activity|small
125b			FLJ25604		GTPase mediated signal transduction
miR-	AI677701	FLJ30829	hypothetical protein	P + T	nucleic acid binding|nucleotide binding
125b			FLJ30829
miR-	NM_004475	FLOT2	flotillin 2	M + P + T	cell adhesion|epidermis development|flotillin
125b					complex|integral to membrane|plasma
					membrane|protein binding
miR-	AA830884	FMR1	fragile X mental	M + T	mRNA binding|mRNA processing|mRNA-nucleus
125b			retardation 1		export|nucleoplasm|polysome|ribosome|soluble
					fraction|transport
miR-	AF305083	FUT4	fucosyltransferase 4	P + T	Golgi apparatus|L-fucose catabolism|alpha(1,3)-
125b			(alpha (1,3)		fucosyltransferase activity|carbohydrate
			fucosyltransferase,		metabolism|integral to
			myeloid-specific)		membrane|membrane|membrane fraction|protein
					amino acid glycosylation|transferase activity,
					transferring glycosyl groups
miR-	X92762	G4.5	tafazzin	M + P + T	acyltransferase activity|heart development|integral to
125b			(cardiomyopathy,		membrane|metabolism|muscle contraction|muscle
			dilated 3A (X-linked);		development
			endocardial
			fibroelastosis 2; Barth
			syndrome)
miR-	NM_012296	GAB2	GRB2-associated	P + T
125b			binding protein 2
miR-	NM_015044	GGA2	golgi associated,	M + T	ADP-ribosylation factor binding|Golgi stack|Golgi
125b			gamma adaptin ear		trans face|clathrin coat of trans-Golgi network
			containing, ARF		vesicle|intra-Golgi transport|intracellular protein
			binding protein 2		transport|intracellular protein
					transport|membrane|protein complex assembly|protein
					transporter activity
miR-	AL049709	GGTL3	gamma-	M + P + T
125b			glutamyltransferase-like 3
miR-	NM_000165	GJA1	gap junction protein,	P + T	cell-cell signaling|connexon channel
125b			alpha 1, 43 kDa		activity|connexon complex|gap junction
			(connexin 43)		assembly|heart development|integral to plasma
					membrane|ion transporter activity|muscle
					contraction|perception of sound|positive regulation of
					I-kappaB kinase/NF-kappaB cascade|protein
					binding|signal transducer activity|transport
miR-	NM_014905	GLS	glutaminase	P + T	glutaminase activity|glutamine catabolism|hydrolase
125b					activity|mitochondrion
miR-	NM_005113	GOLGA5	golgi autoantigen,	P + T	ATP binding|Golgi membrane|cell surface receptor
125b			golgin subfamily a, 5		linked signal transduction|integral to plasma
					membrane|protein amino acid
					phosphorylation|protein-tyrosine kinase activity
miR-	NM_001448	GPC4	glypican 4	M + P + T	cell proliferation|extracellular matrix (sensu
125b					Metazoa)|integral to plasma
					membrane|membrane|morphogenesis
miR-	NM_005296	GPR23	G protein-coupled	M + T	G-protein coupled receptor protein signaling
125b			receptor 23		pathway|integral to plasma membrane|purinergic
					nucleotide receptor activity, G-protein
					coupled|receptor activity|rhodopsin-like receptor
					activity|signal transduction
miR-	U66065	GRB10	growth factor receptor-	M + T	SH3/SH2 adaptor activity|cell-cell
125b			bound protein 10		signaling|cytoplasm|insulin receptor signaling
					pathway|intracellular signaling cascade|plasma
					membrane
miR-	NM_021643	GS3955	GS3955 protein	P + T	ATP binding|protein amino acid
125b					phosphorylation|protein kinase activity|transferase
					activity
miR-	NM_019096	GTPBP2	GTP binding protein 2	M + T	GTP binding|GTPase activity|protein
125b					biosynthesis|small GTPase mediated signal
					transduction
miR-	U78181	hBNaC2	amiloride-sensitive	P + T	amiloride-sensitive sodium channel activity|integral to
125b			cation channel 2,		plasma membrane|ion channel activity|ion
			neuronal		transport|membrane|response to pH|signal
					transduction|sodium ion transport
miR-	NM_005477	HCN4	hyperpolarization	P + T	3′,5′-cAMP binding|cation channel activity|cation
125b			activated cyclic		transport|circulation|integral to plasma
			nucleotide-gated		membrane|membrane|membrane fraction|muscle
			potassium channel 4		contraction|nucleotide binding|potassium ion
					transport|sodium ion transport|voltage-gated
					potassium channel activity
miR-	NM_002112	HDC	histidine decarboxylase	P + T	amino acid metabolism|catecholamine
125b					biosynthesis|histidine decarboxylase activity|histidine
					metabolism|lyase activity
miR-	U64317	HEF1	enhancer of	P + T	actin filament bundle formation|cell adhesion|
125b			filamentation 1 (cas-like		cytokinesis|cytoplasm|cytoskeleton|cytoskeleton
			docking; Crk-associated		organization and biogenesis|integrin-mediated
			substrate related)		signaling pathway|mitosis|nucleus|protein
					binding|regulation of cell cycle|regulation of cell
					growth|signal transduction|spindle
miR-	L38487	hERRa	estrogen-related	P + T	nucleus|regulation of transcription, DNA-
125b			receptor alpha		dependent|steroid binding|steroid hormone receptor
					activity|transcription|transcription factor activity
miR-	AB028943	HIC2	hypermethylated in	P + T	DNA binding|negative regulation of transcription,
125b			cancer 2		DNA-dependent|nucleus|protein C-terminus
					binding|transcription|zinc ion binding
miR-	AL023584	HIVEP2	human	P + T
125b			immunodeficiency virus
			type I enhancer binding
			protein 2
miR-	AL023584	HIVEP2	human	P + T
125b			immunodeficiency virus
			type I enhancer binding
			protein 2
miR-	NM_005342	HMGB3	high-mobility group	P + T	DNA bending activity|DNA
125b			box 3		binding|chromatin|development|nucleus|regulation of
					transcription, DNA-dependent
miR-	AL031295	HMGCL;	lysophospholipase II	M + P + T
125b		HL
miR-	NM_004503	HOXC6	homeo box C6	P + T	development|development|nucleus|regulation of
125b					transcription from RNA polymerase II
					promoter|regulation of transcription, DNA-
					dependent|transcription corepressor
					activity|transcription factor activity
miR-	AA844682	HRD1	HRD1 protein	P + T	protein ubiquitination|ubiquitin ligase
125b					complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	AL136667	HSPC039	HSPC039 protein	P + T	integral to membrane
125b
miR-	AF245044	HT023	hypothetical protein	P + T
125b			HT023
miR-	U13022	Ich-1	caspase 2, apoptosis-	P + T	anti-apoptosis|apoptotic program|caspase
125b			related cysteine		activity|caspase activity|caspase activity|cysteine-type
			protease (neural		peptidase activity|enzyme binding|intracellular|protein
			precursor cell		binding|proteolysis and peptidolysis|proteolysis and
			expressed,		peptidolysis|regulation of apoptosis
			developmentally down-
			regulated 2)
miR-	NM_004513	IL16	interleukin 16	M + P + T	chemotaxis|cytokine activity|extracellular
125b			(lymphocyte		space|immune response|protein binding|sensory
			chemoattractant factor)		perception
miR-	NM_002460	IRF4	interferon regulatory	P + T	RNA polymerase II transcription factor activity|T-cell
125b			factor 4		activation|T-cell
					activation|nucleus|nucleus|nucleus|positive regulation
					of interleukin-10 biosynthesis|positive regulation of
					interleukin-10 biosynthesis|positive regulation of
					interleukin-13 biosynthesis|positive regulation of
					interleukin-13 biosynthesis|positive regulation of
					interleukin-2 biosynthesis|positive regulation of
					interleukin-2 biosynthesis|positive regulation of
					interleukin-4 biosynthesis|positive regulation of
					interleukin-4 biosynthesis|positive regulation of
					transcription|positive regulation of
					transcription|regulation of T-helper cell
					differentiation|regulation of T-helper cell
					differentiation|regulation of transcription, DNA-
					dependent|regulation of transcription, DNA-
					dependent|transcription|transcription factor
					activity|transcription factor activity|transcription
					factor binding|transcription factor
					binding|transcriptional activator
					activity|transcriptional activator activity
miR-	NM_002207	ITGA9	integrin, alpha 9	P + T	cell-matrix adhesion|integral to membrane|integrin
125b					complex|integrin-mediated signaling pathway|protein
					binding|receptor activity
miR-	NM_000212	ITGB3	integrin, beta 3 (platelet	P + T	blood coagulation|cell-matrix adhesion|integrin
125b			glycoprotein IIIa,		complex|integrin-mediated signaling pathway|protein
			antigen CD61)		binding|receptor activity
miR-	NM_021991	JUP	junction plakoglobin	P + T	cell adhesion|cell adhesion|cytoplasm|cytoskeletal
125b					protein binding|cytoskeleton|cytoskeleton|membrane
					fraction|mitotic chromosome condensation|protein
					binding|soluble fraction|structural molecule activity
miR-	AF032897	KCNH7	potassium voltage-gated	P + T	cation transport|integral to
125b			channel, subfamily H		membrane|membrane|potassium ion
			(eag-related), member 7		transport|regulation of transcription, DNA-
					dependent|signal transducer activity|signal
					transduction|voltage-gated potassium channel activity
miR-	NM_002252	KCNS3	potassium voltage-gated	M + P + T	cation transport|delayed rectifier potassium channel
125b			channel, delayed-		activity|membrane|membrane fraction|potassium
			rectifier, subfamily S,		channel regulator activity|potassium ion
			member 3		transport|protein binding|voltage-gated potassium
					channel complex
miR-	NM_014735	KIAA0215	KIAA0215 gene	P + T	DNA binding|regulation of transcription, DNA-
125b			product		dependent
miR-	NM_015288	KIAA0239	KIAA0239 protein	P + T	DNA binding|regulation of transcription, DNA-
125b					dependent
miR-	D87469	KIAA0279	cadherin, EGF LAG	M + P + T	G-protein coupled receptor activity|calcium ion
125b			seven-pass G-type		binding|cell adhesion|development|homophilic cell
			receptor 2 (flamingo		adhesion|integral to
			homolog, Drosophila)		membrane|membrane|neuropeptide signaling
					pathway|receptor activity|signal
					transduction|structural molecule activity
miR-	AB002356	KIAA0358	MAP-kinase activating	P + T	cell surface receptor linked signal
125b			death domain		transduction|cytoplasm|death receptor binding|kinase
					activity|plasma membrane|protein kinase activator
					activity
miR-	NM_014871	KIAA0710	KIAA0710 gene	P + T	cysteine-type endopeptidase activity|exonuclease
125b			product		activity|nucleus|ubiquitin cycle|ubiquitin thiolesterase
					activity|ubiquitin-dependent protein catabolism
miR-	AB 018333	KIAA0790	KIAA0790 protein	P + T	cell cycle|negative regulation of cell cycle
125b
miR-	NM_014912	KIAA0940	KIAA0940 protein	P + T	nucleic acid binding
125b
miR-	AB028957	KIAA1034	KIAA1034 protein	P + T	DNA binding|nucleus|regulation of transcription,
125b					DNA-dependent|transcription factor activity
miR-	NM_014901	KIAA1100	KIAA1100 protein	M + P + T	protein ubiquitination|ubiquitin ligase
125b					complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	AB033016	KIAA1190	hypothetical protein	P + T	DNA binding|nucleic acid binding|nucleus|protein
125b			KIAA1190		binding|regulation of transcription, DNA-
					dependent|zinc ion binding
miR-	AA056548	KIAA1268	KIAA1268 protein	P + T	NAD + ADP-ribosyltransferase
125b					activity|nucleus|protein amino acid ADP-ribosylation
miR-	BE670098	KIAA1594	KIAA1594 protein	M + P + T	cysteine-type endopeptidase activity|ubiquitin
125b					cycle|ubiquitin thiolesterase activity|ubiquitin-
					dependent protein catabolism
miR-	AU157109	KIAA1598	KIAA1598 protein	P + T
125b
miR-	AA772278	KIAA1673	KIAA1673	P + T
125b
miR-	NM_015995	KLF13	Kruppel-like factor 13	P + T	DNA binding|RNA polymerase II transcription factor
125b					activity|nucleus|regulation of transcription, DNA-
					dependent|transcription|transcription from RNA
					polymerase II promoter|zinc ion binding
miR-	NM_016531	KLF3	Kruppel-like factor 3	P + T	development|negative regulation of transcription from
125b			(basic)		RNA polymerase II promoter|nucleus|regulation of
					transcription, DNA-
					dependent|transcription|transcription factor
					activity|zinc ion binding
miR-	BE892574	LACTB	lactamase, beta	P + T	hydrolase activity|integral to membrane|response to
125b					antibiotic
miR-	BE566136	LBP-32	LBP protein 32	P + T
125b
miR-	NM_024090	LCE	long-chain fatty-acyl	P + T	integral to membrane
125b			elongase
miR-	NM_003893	LDB1	LIM domain binding 1	P + T	LIM domain
125b					binding|development|development|negative regulation
					of transcription, DNA-dependent|nucleus|transcription
					cofactor activity|transcriptional repressor activity
miR-	U94354	LFNG	lunatic fringe homolog	M + T	Golgi apparatus|development|extracellular
125b			(Drosophila)		region|integral to
					membrane|membrane|organogenesis|transferase
					activity, transferring glycosyl groups
miR-	NM_002310	LIFR	leukemia inhibitory	M + P + T	cell surface receptor linked signal
125b			factor receptor		transduction|integral to plasma membrane|leukemia
					inhibitory factor receptor activity|membrane|receptor
					activity
miR-	NM_016339	Link-	Link guanine nucleotide	P + T	G-protein coupled receptor protein signaling
125b		GEFII	exchange factor II		pathway|guanyl-nucleotide exchange factor
					activity|membrane fraction|neurogenesis|small
					GTPase mediated signal transduction
miR-	NM_005575	LNPEP	leucyl/cystinyl	P + T	aminopeptidase activity|cell-cell signaling|integral to
125b			aminopeptidase		plasma membrane|membrane alanyl aminopeptidase
					activity|metallopeptidase activity|plasma
					membrane|pregnancy|proteolysis and peptidolysis|zinc
					ion binding
miR-	AL031186	LOC129080	putative emu1	P + T
125b
miR-	AI884701	LOC221002	CG4853 gene product	M + P	guanyl-nucleotide exchange factor activity|small
125b					GTPase mediated signal transduction
miR-	AI953847	LOC255488	Homo sapiens mRNA	P + T	electron transport|electron transporter activity|integral
125b			full length insert cDNA		to membrane|iron ion binding|ligase activity|protein
			clone EUROIMAGE		binding|protein ubiquitination during ubiquitin-
			186647, mRNA		dependent protein catabolism|ubiquitin ligase
			sequence		complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	NM_015899	LOC51054	putative glycolipid	P + T
125b			transfer protein
miR-	AA209239	LOC57406	lipase protein	P + T	aromatic compound metabolism|hydrolase
125b					activity|response to toxin|xenobiotic metabolism
miR-	NM_005576	LOXL1	lysyl oxidase-like 1	M + P + T	copper ion binding|electron transporter
125b					activity|extracellular region|oxidoreductase
					activity|protein modification|protein-lysine 6-oxidase
					activity
miR-	AA584297	LRP4	low density lipoprotein	M + T	calcium ion binding|endocytosis|integral to
125b			receptor-related protein 4		membrane|membrane|receptor activity
miR-	NM_007260	LYPLA2	lysophospholipase II	M + P + T	fatty acid metabolism|hydrolase activity|lipid
125b					metabolism
miR-	NM_004901	LYSAL1	lysosomal apyrase-like 1	P + T	Golgi apparatus|UDP catabolism|apyrase
125b					activity|hydrolase activity|integral to Golgi
					membrane|integral to membrane|lysosome|magnesium
					ion binding|nucleobase, nucleoside, nucleotide and
					nucleic acid metabolism|uridine-diphosphatase
					activity|vacuolar membrane
miR-	NM_002355	M6PR	mannose-6-phosphate	M + P + T	endosome to lysosome transport|integral to plasma
125b			receptor (cation		membrane|lysosome|receptor mediated
			dependent)		endocytosis|transmembrane receptor
					activity|transport|transporter activity
miR-	AB002356	MADD	MAP-kinase activating	P + T	cell surface receptor linked signal
125b			death domain		transduction|cytoplasm|death receptor binding|kinase
					activity|plasma membrane|protein kinase activator
					activity
miR-	NM_016219	MAN1B1	mannosidase, alpha,	P + T	N-linked glycosylation|N-linked
125b			class 1B, member 1		glycosylation|calcium ion binding|calcium ion
					binding|carbohydrate metabolism|endoplasmic
					reticulum|hydrolase activity, acting on glycosyl
					bonds|integral to membrane|mannosyl-
					oligosaccharide 1,2-alpha-mannosidase
					activity|mannosyl-oligosaccharide 1,2-alpha-
					mannosidase activity|membrane|membrane
					fraction|oligosaccharide metabolism
miR-	NM_002446	MAP3K10	mitogen-activated	P + T	ATP binding|JUN kinase kinase kinase
125b			protein kinase kinase		activity|activation of
			kinase 10		JNK|autophosphorylation|induction of
					apoptosis|protein homodimerization activity|protein
					serine/threonine kinase activity|protein-tyrosine
					kinase activity|signal transduction|transferase activity
miR-	NM_002419	MAP3K11	mitogen-activated	M + P + T	ATP binding|G1 phase of mitotic cell cycle|JUN
125b			protein kinase kinase		kinase kinase kinase activity|activation of
			kinase 11		JNK|autophosphorylation|cell
					proliferation|centrosome|microtubule|microtubule-
					based process|protein homodimerization
					activity|protein oligomerization|protein
					serine/threonine kinase activity|protein-tyrosine
					kinase activity|transferase activity
miR-	Z25432	MAPK14	mitogen-activated	P + T	ATP binding|MAP kinase activity|MAP kinase kinase
125b			protein kinase 14		activity|MP kinase activity|antimicrobial humoral
					response (sensu Vertebrata)|cell motility|cell surface
					receptor linked signal
					transduction|chemotaxis|cytoplasm|nucleus|protein
					amino acid phosphorylation|protein kinase
					cascade|protein serine/threonine kinase
					activity|protein-tyrosine kinase activity|response to
					stress|transferase activity
miR-	NM_018650	MARK1	MAP/microtubule	P + T	ATP binding|cytoplasm|cytoskeleton|cytoskeleton
125b			affinity-regulating		organization and biogenesis|magnesium ion
			kinase 1		binding|microtubule cytoskeleton|protein amino acid
					phosphorylation|protein amino acid
					phosphorylation|protein kinase cascade|protein
					serine/threonine kinase activity|protein
					serine/threonine kinase activity|transferase activity
miR-	NM_001879	MASP1	mannan-binding lectin	P + T	calcium ion binding|chymotrypsin
125b			serine protease 1		activity|complement activation|complement
			(C4/C2 activating		activation, classical pathway|extracellular
			component of Ra-		region|immune response|peptidase activity|proteolysis
			reactive factor)		and peptidolysis|trypsin activity
miR-	NM_005911	MAT2A	methionine	P + T	ATP binding|magnesium ion binding|methionine
125b			adenosyltransferase II,		adenosyltransferase activity|one-carbon compound
			alpha		metabolism|transferase activity
miR-	NM_005920	MEF2D	MADS box	P + T	muscle development|nucleus|regulation of
125b			transcription enhancer		transcription, DNA-
			factor 2, polypeptide D		dependent|transcription|transcription coactivator
			(myocyte enhancer		activity|transcription factor activity|transcription from
			factor 2D)		RNA polymerase II promoter
miR-	NM_020149	MEIS2	Meis1, myeloid	M + P	negative regulation of transcription from RNA
125b			ecotropic viral		polymerase II promoter|nucleus|regulation of
			integration site 1		transcription, DNA-dependent|specific RNA
			homolog 2 (mouse)		polymerase II transcription factor
					activity|transcription corepressor activity|transcription
					factor activity|transcription factor activity
miR-	NM_017927	MEN1	mitofusin 1	P + T	GTP binding|GTPase activity|hydrolase
125b					activity|integral to membrane|mitochondrial
					fusion|mitochondrial outer membrane|mitochondrion
miR-	AI139252	MGC16063	ribosomal protein L35a	P + T	JAK-STAT cascadelacute-phase response|calcium ion
125b					binding|cell
					motility|cytoplasm|hematopoietin/interferon-class
					(D200-domain) cytokine receptor signal transducer
					activity|intracellular signaling cascade|negative
					regulation of transcription from RNA polymerase II
					promoter|neurogenesis|nucleus|nucleus|regulation of
					transcription, DNA-dependent|signal transducer
					activity|transcription|transcription factor
					activity|transcription factor activity
miR-	AI862120	MGC21981	hypothetical protein	P + T	membrane
125b			MGC21981
miR-	AL515061	MGC24302	hypothetical protein	P + T
125b			MGC24302
miR-	BE618656	MGC2541	similar to RIKEN	M + P + T
125b			cDNA 2610030J16
			gene
miR-	BC005842	MGC2705	hypothetical protein	P + T
125b			MGC2705
miR-	NM_024293	MGC3035	hypothetical protein	M + P
125b			MGC3035
miR-	NM_017572	MKNK2	MAP kinase-interacting	P + T	ATP binding|ATP binding|cell surface receptor linked
125b			serine/threonine kinase 2		signal transduction|protein amino acid
					phosphorylation|protein amino acid
					phosphorylation|protein kinase cascade|protein
					serine/threonine kinase activity|protein
					serine/threonine kinase activity|protein-tyrosine
					kinase activity|regulation of translation|response to
					stress|transferase activity
miR-	NM_005439	MLF2	myeloid leukemia factor 2	P + T	defense response|nucleus
125b
miR-	NM_007359	MLN51	MLN51 protein	P + T	mRNA processing|mRNA-nucleus
125b					export|molecular_function unknown|nucleus|transport
miR-	NM_002442	MSI1	musashi homolog 1	M + P + T	RNA binding|neurogenesis|nucleotide binding|nucleus
125b			(Drosophila)
miR-	NM_021090	MTMR3	myotubularin related	M + P + T	cytoplasm|hydrolase activity|inositol or
125b			protein 3		phosphatidylinositol phosphatase
					activity|membrane|membrane fraction|phospholipid
					dephosphorylation|protein amino acid
					dephosphorylation|protein serine/threonine
					phosphatase activity|protein tyrosine phosphatase
					activity|protein tyrosine/serine/threonine phosphatase
					activity|zinc ion binding
miR-	AK024501	MXD4	MAX dimerization	M + P + T	DNA binding|negative regulation of cell
125b			protein 4		proliferation|negative regulation of transcription from
					RNA polymerase II promoter|nucleus|protein
					binding|regulation of transcription, DNA-
					dependent|transcription|transcription corepressor
					activity
miR-	AB020642	MYT1	myelin transcription	M + P + T	nucleus|regulation of transcription, DNA-
125b			factor 1		dependent|transcription|transcription factor
					activity|zinc ion binding
miR-	NM_004540	NCAM2	neural cell adhesion	P + T	cell adhesion|integral to membrane|membrane|neuron
125b			molecule 2		adhesion|plasma membrane|protein binding
miR-	NM_012338	NET-2	transmembrane 4	P + T	integral to membrane|membrane fraction
125b			superfamily member
			tetraspan NET-2
miR-	U84246	NEU1	sialidase 1 (lysosomal	P + T	carbohydrate metabolism|exo-alpha-sialidase
125b			sialidase)		activity|hydrolase activity, acting on glycosyl
					bonds|lysosome
miR-	AI824012	NRIP1	nuclear receptor	P + T	nucleus|regulation of transcription, DNA-
125b			interacting protein 1		dependent|transcription|transcription coactivator
					activity
miR-	D81048	NRM	nurim (nuclear envelope	P + T
125b			membrane protein)
miR-	BC001794	NUMBL	numb homolog	P + T	neurogenesis
125b			(Drosophila)-like
miR-	AB020713	NUP210	nucleoporin 210	P + T	development|nucleus
125b
miR-	NM_002537	OAZ2	ornithine decarboxylase	M + P + T	ornithine decarboxylase inhibitor activity|polyamine
125b			antizyme 2		metabolism
miR-	NM_024586	OSBPL9	oxysterol binding	P + T	lipid transport|steroid metabolism
125b			protein-like 9
miR-	U64661	PABP	ESTs, Highly similar to	P + T
125b			PAB1_HUMAN
			Polyadenylate-binding
			protein 1 (Poly(A)-
			binding protein 1)
			(PABP 1) (PABP1)
			[H. sapiens]
miR-	AK000003	PCQAP	PC2 (positive cofactor	P + T
125b			2, multiprotein
			complex) glutamine/Q-
			rich-associated protein
miR-	NM_004716	PCSK7	proprotein convertase	M + P + T	integral to Golgi membrane|integral to
125b			subtilisin/kexin type 7		membrane|peptidase activity|peptidase activity|peptide
					hormone processing|proteolysis and
					peptidolysis|subtilase activity
miR-	NM_006201	PCTK1	PCTAIRE protein	M + P + T	ATP binding|protein amino acid
125b			kinase 1		phosphorylation|protein amino acid
					phosphorylation|protein serine/threonine kinase
					activity|protein serine/threonine kinase
					activity|regulation of cell cycle|transferase activity
miR-	NM_021213	PCTP	phosphatidylcholine	M + P + T	cytosol|lipid binding|lipid
125b			transfer protein		transport|phosphatidylcholine transporter activity
miR-	NM_021255	PELI2	pellino homolog 2	M + P + T
125b			(Drosophila)
miR-	NM_002646	PIK3C2B	phosphoinositide-3-	P + T	inositol or phosphatidylinositol kinase
125b			kinase, class 2, beta		activity|intracellular signaling
			polypeptide		cascade|microsome (phosphatidylinositol 3-kinase
					activity|phosphatidylinositol-4-phosphate 3-kinase
					activity|phosphoinositide 3-kinase complex|plasma
					membrane|transferase activity
miR-	NM_003628	PKP4	plakophilin 4	P + T	cell adhesion|cytoskeleton|intercellular
125b					junction|protein binding|structural molecule activity
miR-	NM_006718	PLAGL1	pleiomorphic adenoma	P + T	DNA binding|cell cycle arrest|induction of
125b			gene-like 1		apoptosis|nucleic acid binding|nucleus|regulation of
					transcription, DNA-dependent|transcription|zinc ion
					binding
miR-	AI457120	PPAT	phosphoribosyl	P + T	amidophosphoribosyltransferase activity|glutamine
125b			pyrophosphate		metabolism|magnesium ion
			amidotransferase		binding|metabolism|nucleoside metabolism|purine
					base biosynthesis|purine nucleotide
					biosynthesis|transferase activity, transferring glycosyl
					groups
miR-	NM_002719	PPP2R5C	protein phosphatase 2,	P + T	hydrolase activity|nucleus|phosphoprotein
125b			regulatory subunit B		phosphatase activity|protein phosphatase type 2A
			(B56), gamma isoform		complex|protein phosphatase type 2A complex|protein
					phosphatase type 2A regulator activity|protein
					phosphatase type 2A regulator activity|signal
					transduction|signal transduction
miR-	AL022067	PRDM1	PR domain containing	P + T
125b			1, with ZNF domain
miR-	U23736	PRDM2	PR domain containing	P + T	DNA binding|metal ion
125b			2, with ZNF domain		binding|nucleus|nucleus|regulation of
					transcription|regulation of transcription, DNA-
					dependent|transcription factor activity|transcription
					regulator activity|zinc ion binding|zinc ion binding
miR-	AF083033	PRKRA	protein kinase,	P + T	double-stranded RNA binding|enzyme activator
125b			interferon-inducible		activity|immune response|intracellular|kinase
			double stranded RNA		activity|negative regulation of cell
			dependent activator		proliferation|response to virus|signal transducer
					activity|signal transduction
miR-	NM_014369	PTPN18	protein tyrosine	P + T	hydrolase activity|non-membrane spanning protein
125b			phosphatase, non-		tyrosine phosphatase activity|protein amino acid
			receptor type 18 (brain-		dephosphorylation|protein amino acid
			derived)		dephosphorylation|protein tyrosine phosphatase
					activity
miR-	AI762627	PTPRF	protein tyrosine	P + T	cell adhesion|hydrolase activity|integral to
125b			phosphatase, receptor		membrane|integral to plasma membrane|protein
			type, F		amino acid dephosphorylation|protein binding|protein
					tyrosine phosphatase activity|receptor
					activity|transmembrane receptor protein tyrosine
					phosphatase activity|transmembrane receptor protein
					tyrosine phosphatase signaling pathway
miR-	NM_002840	PTPRF	protein tyrosine	P + T	cell adhesion|hydrolase activity|integral to
125b			phosphatase, receptor		membrane|integral to plasma membrane|protein
			type, F		amino acid dephosphorylation|protein binding|protein
					tyrosine phosphatase activity|receptor
					activity|transmembrane receptor protein tyrosine
					phosphatase activity|transmembrane receptor protein
					tyrosine phosphatase signaling pathway
miR-	AF142419	QKI	homolog of mouse	P + T
125b			quaking QKI (KH
			domain RNA binding
			protein)
miR-	NM_004283	RAB3D	RAB3D, member RAS	P + T	GTP binding|GTPase activity|exocytosis|hemocyte
125b			oncogene family		development|protein transport|small GTPase mediated
					signal transduction
miR-	BC002510	RAB6B	RAB6B, member RAS	P + T	GTP binding|GTPase activity|Golgi
125b			oncogene family		apparatus|intracellular protein transport|retrograde
					transport, Golgi to ER|small GTPase mediated signal
					transduction
miR-	AK022662	RASAL2	RAS protein activator	P + T	GTPase activator activity|Ras GTPase activator
125b			like 2		activity|signal transduction
miR-	NM_004841	RASAL2	RAS protein activator	P + T	GTPase activator activity|Ras GTPase activator
125b			like 2		activity|signal transduction
miR-	NM_016090	RBM7	RNA binding motif	P + T	RNA binding|meiosis|nucleic acid binding|nucleotide
125b			protein 7		binding
miR-	NM_006268	REQ	requiem, apoptosis	M + P + T	DNA binding|apoptosis|induction of apoptosis by
125b			response zinc finger		extracellular signals|nucleus|protein
			gene		ubiquitination|regulation of transcription, DNA-
					dependent|transcription|ubiquitin ligase
					complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	NM_000449	RFX5	regulatory factor X, 5	P + T	nucleus|regulation of transcription, DNA-
125b			(influences HLA class		dependent|transcription|transcription coactivator
			II expression)		activity|transcription factor activity|transcription from
					RNA polymerase II promoter
miR-	NM_003721	RFXANK	regulatory factor X-	P + T	humoral immune response|nucleus|regulation of
125b			associated ankyrin-		transcription, DNA-
			containing protein		dependent|transcription|transcription coactivator
					activity|transcription factor activity|transcription from
					RNA polymerase II promoter
miR-	NM_014746	RNF144	likely ortholog of	P + T	nucleus|protein ubiquitination|ubiquitin ligase
125b			mouse ubiquitin		complex|ubiquitin-protein ligase activity|zinc ion
			conjugating enzyme 7		binding
			interacting protein 4
miR-	NM_014771	RNF40	ring finger protein 40	M + P + T	protein ubiquitination|ubiquitin ligase
125b					complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	AL109955	RNPC1	RNA-binding region	P + T
125b			(RNP1, RRM)
			containing 1
miR-	AF116627	RPL29	ribosomal protein L29	M + T
125b
miR-	NM_002953	RPS6KA1	ribosomal protein S6	M + P + T	ATP binding|protein amino acid
125b			kinase, 90 kDa,		phosphorylation|protein serine/threonine kinase
			polypeptide 1		activity|protein serine/threonine kinase
					activity|protein-tyrosine kinase activity|signal
					transduction|transferase activity
miR-	NM_000332	SCA1	spinocerebellar ataxia 1	P + T	RNA binding|cytoplasm|nucleus
125b			(olivopontocerebellar
			ataxia 1, autosomal
			dominant, ataxin 1)
miR-	NM_012429	SEC14L2	SEC14-like 2	P + T	cytoplasm|intracellular protein
125b			(S. cerevisiae)		transport|membrane|nucleus|phospholipid
					binding|positive regulation of transcription, DNA-
					dependent|protein carrier activity|regulation of
					cholesterol biosynthesis|transcription|transcriptional
					activator activity|transport|vitamin E binding
miR-	NM_005065	SEL1L	sel-1 suppressor of lin-	P + T	catalytic activity|integral to membrane
125b			12-like (C. elegans)
miR-	NM_017789	SEMA4C	sema domain,	M + P + T	cell differentiation|integral to
125b			immunoglobulin		membrane|membrane|neurogenesis|receptor activity
			domain (Ig),
			transmembrane domain
			(TM) and short
			cytoplasmic domain,
			(semaphorin) 4C
miR-	NM_006378	SEMA4D	sema domain,	P + T	anti-apoptosis|cell adhesion|cell
125b			immunoglobulin		differentiation|immune response|integral to
			domain (Ig),		membrane|membrane|neurogenesis|receptor activity
			transmembrane domain
			(TM) and short
			cytoplasmic domain,
			(semaphorin) 4D
miR-	BE622841	SENP2	sentrin-specific protease	M + P
125b
miR-	NM_003011	SET	SET translocation	M + T	DNA replication|endoplasmic reticulum|histone
125b			(myeloid leukemia-		binding|negative regulation of histone
			associated)		acetylation|nucleocytoplasmic transport|nucleosome
					assembly|nucleosome disassembly|nucleus|perinuclear
					region|protein phosphatase inhibitor activity|protein
					phosphatase type 2A regulator activity
miR-	NM_006275	SFRS6	splicing factor,	P + T	RNA binding|mRNA splice site selection|nuclear
125b			arginine/serine-rich 6		mRNA splicing, via spliceosome|nucleotide
					binding|nucleus
miR-	AF015043	SH3BP4	SH3-domain binding	P + T	cell cycle|endocytosis|nucleus|signal transducer
125b			protein 4		activity
miR-	NM_016538	SIRT7	sirtuin silent mating	P + T	DNA binding|chromatin silencing|chromatin silencing
125b			type information		complex|hydrolase activity|regulation of transcription,
			regulation 2 homolog 7		DNA-dependent
			(S. cerevisiae)
miR-	NM_020309	SLC17A7	solute carrier family 17	P + T	integral to membrane|phosphate transport|sodium-
125b			(sodium-dependent		dependent phosphate transporter
			inorganic phosphate		activity|transport|transporter activity
			cotransporter), member 7
miR-	NM_013272	SLC21A11	solute carrier family 21	P + T	integral to membrane|ion
125b			(organic anion		transport|membrane|transporter activity
			transporter), member 11
miR-	AK000722	SLC27A4	solute carrier family 27	P + T	catalytic activity|fatty acid transport|fatty acid
125b			(fatty acid transporter),		transporter activity|ligase activity|lipid
			member 4		metabolism|lipid transport|metabolism
miR-	NM_003759	SLC4A4	solute carrier family 4,	P + T	anion transport|inorganic anion exchanger
125b			sodium bicarbonate		activity|integral to membrane|integral to plasma
			cotransporter, member 4		membrane|membrane|sodium:bicarbonate symporter
					activity|transport
miR-	NM_003045	SLC7A1	solute carrier family 7	P + T	amino acid metabolism|amino acid permease
125b			(cationic amino acid		activity|amino acid transport|basic amino acid
			transporter, y+ system),		transporter activity|integral to plasma
			member 1		membrane|membrane|receptor activity|transport
miR-	NM_003983	SLC7A6	solute carrier family 7	P + T	amino acid metabolism|amino acid transport|amino
125b			(cationic amino acid		acid-polyamine transporter activity|integral to plasma
			transporter, y+ system),		membrane|plasma membrane|protein complex
			member 6		assembly|transport
miR-	AF113019	SMARCD2	SWI/SNF related,	M + P + T	chromatin remodeling|nucleoplasm|regulation of
125b			matrix associated, actin		transcription from RNA polymerase II
			dependent regulator of		promoter|transcription|transcription coactivator
			chromatin, subfamily d,		activity
			member 2
miR-	NM_005985	SNAI1	snail homolog 1	P + T	DNA binding|cartilage
125b			(Drosophila)		condensation|development|neurogenesis|nucleus|zinc
					ion binding
miR-	AB037750	SORCS2	VPS10 domain receptor	P + T	integral to membrane|intracellular protein
125b			protein		transport|membrane|membrane|neuropeptide receptor
					activity|neuropeptide signaling pathway|protein
					binding|protein transporter activity|sugar binding
miR-	BE742268	SORT1	sortilin 1	P + T	endocytosis|endosome|integral to membrane|integral
125b					to membrane|intracellular protein
					transport|membrane|neurotensin receptor activity, G-
					protein coupled|protein transporter activity|receptor
					activity
miR-	AI360875	SOX11	SRY (sex determining	M + T	DNA binding|neurogenesis|nucleus|regulation of
125b			region Y)-box 11		transcription, DNA-dependent|transcription
miR-	AU121035	SP1	Sp1 transcription factor	P + T	DNA binding|RNA polymerase II transcription factor
125b					activity|nucleus|regulation of transcription, DNA-
					dependent|transcription|transcriptional activator
					activity|zinc ion binding
miR-	NM_003131	SRF	serum response factor	M + T	RNA polymerase II transcription factor
125b			(c-fos serum response		activity|nucleus|regulation of transcription from RNA
			element-binding		polymerase II promoter|signal
			transcription factor)		transduction|transcription|transcription factor activity
miR-	NM_005637	SS18	synovial sarcoma	P + T	nucleus
125b			translocation,
			chromosome 18
miR-	AF343880	SSX2	synovial sarcoma, X	P + T	nucleus
125b			breakpoint 2
miR-	NM_014682	ST18	suppression of	P + T	nucleus|regulation of transcription, DNA-
125b			tumorigenicity 18		dependent|transcription factor activity
			(breast carcinoma) (zinc
			finger protein)
miR-	AA128023	STARD13	START domain	P + T
125b			containing 13
miR-	BC000627	STAT3	signal transducer and	P + T	JAK-STAT cascade|acute-phase response|calcium ion
125b			activator of		binding|cell
			transcription 3 (acute-		motility|cytoplasm|hematopoietin/interferon-class
			phase response factor)		(D200-domain) cytokine receptor signal transducer
					activity|intracellular signaling cascade|negative
					regulation of transcription from RNA polymerase II
					promoter|neurogenesis|nucleus|nucleus|regulation of
					transcription, DNA-dependent|signal transducer
					activity|transcription|transcription factor
					activity|transcription factor activity
miR-	NM_003155	STC1	stanniocalcin 1	P + T	calcium ion homeostasis|cell surface receptor linked
125b					signal transduction|cell-cell signaling|extracellular
					region|hormone activity|response to nutrients
miR-	NM_003173	SUV39H1	suppressor of	P + T	DNA replication and chromosome cycle|S-
125b			variegation 3-9		adenosylmethionine-dependent methyltransferase
			homolog 1 (Drosophila)		activity|chromatin|chromatin assembly or
					disassembly|chromatin binding|chromatin
					modification|condensed nuclear chromosome|histone
					lysine N-methyltransferase activity (H3-K9
					specific)|histone-lysine N-methyltransferase
					activity|methyltransferase
					activity|nucleus|nucleus|protein binding|transferase
					activity|zinc ion binding
miR-	AW139618	SYN2	synapsin II	P + T	neurotransmitter secretion|synapse|synaptic
125b					transmission|synaptic vesicle
miR-	R60550	TAF5L	TAF5-like RNA	M + P + T	nucleus|regulation of transcription, DNA-
125b			polymerase II,		dependent|transcription factor activity|transcription
			p300/CBP-associated		from RNA polymerase II promoter
			factor (PCAF)-
			associated factor,
			65 kDa
miR-	AF220509	TAF9L	TAF9-like RNA	P + T	DNA binding|nucleus|regulation of transcription,
125b			polymerase II, TATA		DNA-dependent|transcription factor TFIID
			box binding protein		complex|transcription initiation
			(TBP)-associated factor,
			31 kDa
miR-	NM_000116	TAZ	tafazzin	M + P + T	acyltransferase activity|heart development|integral to
125b			(cardiomyopathy,		membrane|metabolism|muscle contraction|muscle
			dilated 3A (X-linked);		development
			endocardial
			fibroelastosis 2; Barth
			syndrome)
miR-	NM_018488	TBX4	T-box 4	P + T	development|nucleus|regulation of transcription,
125b					DNA-dependent|transcription|transcription factor
					activity
miR-	NM_012249	TC10	ras-like protein TC10	M + T	GTP binding|GTPase activity|plasma membrane|small
125b					GTPase mediated signal transduction
miR-	BG387172	TEAD2	TEA domain family	P + T	nucleus|nucleus|regulation of transcription, DNA-
125b			member 2		dependent|regulation of transcription, DNA-
					dependent|transcription|transcription factor
					activity|transcription factor activity
miR-	U06935	TEF	thyrotrophic embryonic	P + T	RNA polymerase II transcription factor
125b			factor		activity|nucleus|regulation of transcription from RNA
					polymerase II promoter|rhythmic
					process|transcription|transcription factor activity
miR-	NM_006464	TGOLN2	trans-golgi network	P + T	Golgi trans face|integral to membrane|transport
125b			protein 2		vesicle
miR-	BE219311	TIMM22	translocase of inner	P + T	integral to membrane|mitochondrial inner
125b			mitochondrial		membrane|mitochondrion|protein transport|protein
			membrane 22 homolog		transporter activity
			(yeast)
miR-	NM_003326	TNFSF4	tumor necrosis factor	P + T	cell-cell signaling|immune response|integral to plasma
125b			(ligand) superfamily,		membrane|membrane|positive regulation of cell
			member 4 (tax-		proliferation|signal transduction|tumor necrosis factor
			transcriptionally		receptor binding
			activated glycoprotein
			1, 34 kDa)
miR-	AA873275	TOR2A	torsin family 2, member A	P + T	ATP binding|GTP cyclohydrolase I
125b					activity|biosynthesis|chaperone cofactor dependent
					protein folding|endoplasmic reticulum|nucleoside-
					triphosphatase activity|nucleotide binding
miR-	AW341649	TP53INP1	tumor protein p53	M + P + T	apoptosis|nucleus
125b			inducible nuclear
			protein 1
miR-	NM_014112	TRPS1	trichorhinophalangeal	P + T	NLS-bearing substrate-nucleus
125b			syndrome I		import|nucleus|regulation of transcription, DNA-
					dependent|skeletal
					development|transcription|transcription factor
					activity|transcription from RNA polymerase II
					promoter|zinc ion binding
miR-	NM_001070	TUBG1	tubulin, gamma 1	P + T	GTP binding|GTPase activity|centrosome|condensed
125b					nuclear chromosome|gamma-tubulin complex|meiotic
					spindle organization and
					biogenesis|microtubule|microtubule
					nucleation|microtubule-based movement|mitotic
					spindle organization and biogenesis|polar
					microtubule|protein binding|protein
					polymerization|spindle pole body|structural
					constituent of cytoskeleton
miR-	NM_003330	TXNRD1	thioredoxin reductase 1	P + T	FAD binding|cell redox
125b					homeostasis|cytoplasm|disulfide oxidoreductase
					activity|electron transport|electron transporter
					activity|oxidoreductase activity, acting on NADH or
					NADPH, disulfide as acceptor|signal
					transduction|thioredoxin-disulfide reductase activity
miR-	BC004862	UBE2R2	ubiquitin-conjugating	P + T	ligase activity|ubiquitin conjugating enzyme
125b			enzyme E2R 2		activity|ubiquitin cycle|ubiquitin-protein ligase
					activity
miR-	NM_003728	UNC5C	unc-5 homolog B	P + T	apoptosis|axon guidance|brain
125b			(C. elegans)		development|development|integral to membrane |netrin
					receptor activity|protein binding|receptor
					activity|signal transduction
miR-	NM_003369	UVRAG	UV radiation resistance	P + T	DNA repair|cytoplasm
125b			associated gene
miR-	AF195514	VPS4B	vacuolar protein sorting	M + P + T	ATP binding|ATPase activity,
125b			4B (yeast)		coupled|membrane|membrane fusion|nucleoside-
					triphosphatase activity|nucleotide binding|peroxisome
					organization and biogenesis|protein binding|regulation
					of transcription, DNA-dependent
miR-	R51061	VTS58635	mitogen-activated	P + T	GTP binding|small GTPase mediated signal
125b			protein kinase kinase		transduction
			kinase kinase 1
miR-	NM_004184	WARS	tryptophanyl-tRNA	M + T	ATP binding|cytoplasm|ligase activity|negative
125b			synthetase		regulation of cell proliferation|protein
					biosynthesis|soluble fraction|tryptophan-tRNA ligase
					activity|tryptophanyl-tRNA
					aminoacylation|tryptophanyl-tRNA aminoacylation
miR-	NM_005433	YES1	v-yes-1 Yamaguchi	P + T	ATP binding|intracellular signaling cascade|protein
125b			sarcoma viral oncogene		amino acid phosphorylation|protein-tyrosine kinase
			homolog 1		activity|transferase activity
miR-	NM_017740	ZDHHC7	zinc finger, DHHC	P + T	integral to membrane|metal ion binding
125b			domain containing 7
miR-	BF525395	ZFP385	likely ortholog of	M + P + T	DNA binding|nucleic acid binding|nucleus|regulation
125b			mouse zinc finger		of transcription, DNA-dependent|transcription|zinc
			protein 385		ion binding
miR-	NM_007345	ZNF236	zinc finger protein 236	P + T	nucleus|regulation of transcription, DNA-
125b					dependent|transcription|transcription factor
					activity|zinc ion binding
miR-	NM_012482	ZNF281	zinc finger protein 281	M + P + T	DNA binding|DNA-directed RNA polymerase II, core
125b					complex|negative regulation of transcription from
					RNA polymerase II promoter|nucleus|regulation of
					transcription, DNA-dependent|specific RNA
					polymerase II transcription factor
					activity|transcription|zinc ion binding
miR-	NM_003427	ZNF76	zinc finger protein 76	P + T	DNA binding|nucleus|regulation of transcription from
125b			(expressed in testis)		RNA polymerase II promoter|regulation of
					transcription from RNA polymerase III
					promoter|transcription|zinc ion binding
miR-	NM_022465	ZNFN1A4	zinc finger protein,	M + P + T	nucleic acid binding|nucleus|transcription factor
125b			subfamily 1A, 4 (Eos)		activity|transcriptional repressor activity|zinc ion
					binding
miR-	NM_005502	ABCA1	ATP-binding cassette,	P + T	ATP binding|ATP binding|ATPase activity|anion
145			sub-family A (ABC1),		transporter activity|cholesterol metabolism|integral to
			member 1		plasma membrane|lipid metabolism|membrane
					fraction|nucleotide binding|steroid metabolism|sterol
					transporter activity|transport|transport
miR-	AL527773	ABR	active BCR-related	M + P + T	GTPase activator activity|guanyl-nucleotide exchange
145			gene		factor activity|small GTPase mediated signal
					transduction
miR-	NM_001616	ACVR2	activin A receptor, type	M + P + T	ATP binding|integral to plasma
145			II		membrane|membrane|protein amino acid
					phosphorylation|receptor activity|transferase
					activity|transforming growth factor beta receptor
					activity|transmembrane receptor protein
					serine/threonine kinase signaling pathway
miR-	NM_003183	ADAM17	a disintegrin and	P + T	cell-cell signaling|integral to plasma
145			metalloproteinase		membrane|metalloendopeptidase activity|proteolysis
			domain 17 (tumor		and peptidolysis|zinc ion binding
			necrosis factor, alpha,
			converting enzyme)
miR-	NM_019903	ADD3	adducin 3 (gamma)	M + P + T	calmodulin binding|cytoskeleton|membrane|structural
145					constituent of cytoskeleton
miR-	AB003476	AKAP12	A kinase (PRKA)	P + T	G-protein coupled receptor protein signaling
145			anchor protein (gravin)		pathway|cytoplasm|protein binding|protein kinase A
			12		binding|protein targeting|signal transduction
miR-	NM_016201	AMOTL2	angiomotin like 2	M + P + T
145
miR-	NM_001128	AP1G1	adaptor-related protein	M + P + T	Golgi apparatus|binding|clathrin coat of trans-Golgi
145			complex 1, gamma 1		network vesicle|coated pit|endocytosis|intracellular
			subunit		protein transport|intracellular protein
					transport|membrane coat adaptor complex|protein
					complex assembly|transporter activity
miR-	NM_001284	AP3S1	adaptor-related protein	M + P + T	Golgi apparatus|clathrin vesicle coat|insulin receptor
145			complex 3, sigma 1		signaling pathway|intracellular protein
			subunit		transport|membrane coat adaptor
					complex|transport|transport vesicle|transporter activity
miR-	NM_006380	APPBP2	amyloid beta precursor	M + P + T	binding|cytoplasm|intracellular protein
145			protein (cytoplasmic		transport|membrane|microtubule associated
			tail) binding protein 2		complex|microtubule motor activity|nucleus
miR-	AB037845	ARHGAP10	Rho-GTPase activating	M + T	protein binding
145			protein 10
miR-	AL516350	ARPC5	actin related protein 2/3	P + T	Arp2/3 protein complex|actin cytoskeleton
145			complex, subunit 5,		organization and biogenesis|cell
			16 kDa		motility|cytoplasm|cytoskeleton|regulation of actin
					filament polymerization|structural constituent of
					cytoskeleton
miR-	U72937	ATRX	alpha	M + T	ATP binding|DNA binding|DNA helicase
145			thalassemia/mental		activity|DNA methylation|DNA recombination|DNA
			retardation syndrome		repair|chromosome organization and biogenesis
			X-linked (RAD54		(sensu Eukaryota)|helicase activity|hydrolase
			homolog, S. cerevisiae)		activity|nuclear heterochromatin|nucleus|perception of
					sound|regulation of transcription, DNA-
					dependent|transcription factor activity
miR-	NM_021813	BACH2	BTB and CNC	P + T	DNA binding|nucleus|protein binding|regulation of
145			homology 1, basic		transcription, DNA-dependent|transcription
			leucine zipper
			transcription factor 2
miR-	NM_013449	BAZ2A	bromodomain adjacent	P + T	DNA binding|chromatin remodeling|nucleolus
145			to zinc finger domain,		organizer complex|nucleus|regulation of transcription,
			2A		DNA-dependent|transcription|transcription regulator
					activity
miR-	NM_007005	BCE-1	BCE-1 protein	M + P	frizzled signaling pathway|molecular_function
145					unknown|nucleus|nucleus|regulation of
					transcription|regulation of transcription, DNA-
					dependent
miR-	NM_003458	BSN	bassoon (presynaptic	P + T	cytoskeleton|metal ion binding|nucleus|structural
145			cytomatrix protein)		constituent of cytoskeleton|synapse|synaptic
					transmission|synaptosome
miR-	NM_013279	C11orf9	chromosome 11 open	M + P + T
145			reading frame 9
miR-	NM_024643	C14orf140	hypothetical protein	P + T
145			FLJ23093
miR-	NM_018270	C20orf20	chromosome 20 open	P + T	chromatin modification|nucleus|regulation of cell
145			reading frame 20		growth|regulation of transcription, DNA-
					dependent|transcription
miR-	NM_004276	CABP1	calcium binding protein	P + T	calcium ion binding|calcium ion binding|enzyme
145			1 (calbrain)		inhibitor activity
miR-	NM_001755	CBFB	core-binding factor,	M + P + T	RNA polymerase II transcription factor
145			beta subunit		activity|nucleus|transcription coactivator
					activity|transcription factor activity|transcription from
					RNA polymerase II promoter
miR-	NM_001759	CCND2	cyclin D2	P + T	cytokinesis|nucleus|regulation of cell cycle
145
miR-	NM_020307	CCNL1	cyclin L ania-6a	M + P + T	cell cycle|regulation of cell cycle
145
miR-	AL118798	CD47	CD47 antigen (Rh-	P + T	cell-matrix adhesion|integral to plasma
145			related antigen,		membrane|integrin-mediated signaling
			integrin-associated		pathway|plasma membrane|protein binding
			signal transducer)
miR-	BF576053	CFL2	cofilin 2 (muscle)	M + P + T	actin binding|cytoskeleton|nucleus
145
miR-	AA835485	CKLiK	CamKI-like protein	P + T	ATP binding|calcium- and calmodulin-dependent
145			kinase		protein kinase activity|calmodulin
					binding|nucleus|protein amino acid
					phosphorylation|protein serine/threonine kinase
					activity|transferase activity
miR-	NM_004921	CLCA3	chloride channel,	P + T	extracellular space|transport|transporter activity
145			calcium activated,
			family member 3
miR-	NM_001326	CSTF3	cleavage stimulation	M + P + T	RNA binding|binding|mRNA cleavage|mRNA
145			factor, 3′ pre-RNA,		polyadenylylation|nucleus
			subunit 3, 77 kDa
miR-	NM_020248	CTNNBIP1	catenin, beta interacting	P + T	Wnt receptor signaling pathway|beta-catenin
145			protein 1		binding|cell
					proliferation|development|nucleus|regulation of
					transcription, DNA-dependent|signal transduction
miR-	AW772082	DACH	dachshund homolog	P + T	DNA binding|development|eye morphogenesis (sensu
145			(Drosophila)		Endopterygota)|nucleus|regulation of transcription,
					DNA-dependent|transcription
miR-	NM_004393	DAG1	dystroglycan 1	M + P + T	actin cytoskeleton|calcium ion binding|extracellular
145			(dystrophin-associated		matrix (sensu Metazoa)|integral to plasma
			glycoprotein 1)		membrane|laminin receptor activity|membrane
					fraction|muscle contraction|plasma membrane|protein
					binding|protein complex assembly
miR-	NM_003887	DDEF2	development and	P + T	GTPase activator activity|Golgi apparatus|regulation
145			differentiation		of GTPase activity
			enhancing factor 2
miR-	AL080239	DKFZp547M2010	hypothetical protein	M + P + T
145			DKFZp547M2010
miR-	AL137517	DKFZp564O1278	hypothetical protein	P + T	integral to membrane
145			DKFZp564O1278
miR-	NM_001386	DPYSL2	dihydropyrimidinase-	P + T	dihydropyrimidinase activity|hydrolase
145			like 2		activity|neurogenesis|nucleobase, nucleoside,
					nucleotide and nucleic acid metabolism|signal
					transduction
miR-	BC003143	DUSP6	dual specificity	P + T	MAP kinase phosphatase activity|cytoplasm|hydrolase
145			phosphatase 6		activity|inactivation of MAPK|protein amino acid
					dephosphorylation|protein serine/threonine
					phosphatase activity|protein tyrosine phosphatase
					activity|regulation of cell cycle|soluble fraction
miR-	D86550	DYRK1A	dual-specificity	P + T	ATP binding|neurogenesis|nucleus|protein amino acid
145			tyrosine-(Y)-		phosphorylation|protein serine/threonine kinase
			phosphorylation		activity|protein-tyrosine kinase activity|transferase
			regulated kinase 1A		activity
miR-	NM_001967	EIF4A2	eukaryotic translation	M + P + T	ATP binding|ATP-dependent helicase activity|DNA
145			initiation factor 4A,		binding|RNA binding|eukaryotic translation initiation
			isoform 2		factor 4F complex|hydrolase activity|protein
					biosynthesis|regulation of translational
					initiation|translation initiation factor activity
miR-	NM_001417	EIF4B	eukaryotic translation	M + T	RNA binding|eukaryotic translation initiation factor
145			initiation factor 4B		4F complex|nucleic acid binding|nucleotide
					binding|protein biosynthesis|regulation of translational
					initiation|translation initiation factor
					activity|translation initiation factor activity
miR-	BC005057	EIF4EBP2	eukaryotic translation	P + T	eukaryotic initiation factor 4E binding|negative
145			initiation factor 4E		regulation of protein biosynthesis|negative regulation
			binding protein 2		of translational initiation|regulation of translation
miR-	NM_020909	EPB41L5	erythrocyte membrane	P + T	binding|cytoplasm|cytoskeletal protein
145			protein band 4.1 like 5		binding|cytoskeleton|membrane
miR-	NM_005797	EVA1	epithelial V-like antigen 1	P + T	cell adhesion|cytoskeleton|homophilic cell
145					adhesion|integral to
					membrane|membrane|morphogenesis|protein binding
miR-	NM_022977	FACL4	fatty-acid-Coenzyme A	M + P + T	fatty acid metabolism|integral to membrane|learning
145			ligase, long-chain 4		and/or memory|ligase activity|lipid metabolism|long-
					chain-fatty-acid-CoA ligase activity|magnesium ion
					binding|metabolism
miR-	AL042120	FHOD2	formin homology 2	M + P	Rho GTPase binding|actin binding|actin cytoskeleton
145			domain containing 2		organization and biogenesis|cell organization and
					biogenesis|nucleus|regulation of transcription, DNA-
					dependent|transcription factor activity|translation
					initiation factor activity|translational initiation
miR-	NM_002013	FKBP3	FK506 binding protein	P + T	FK506 binding|isomerase activity|nucleus|peptidyl-
145			3, 25 kDa		prolyl cis-trans isomerase activity|protein
					folding|receptor activity
miR-	NM_002017	FLI1	Friend leukemia virus	M + P + T	hemostasis|nucleus|organogenesis|regulation of
145			integration 1		transcription, DNA-
					dependent|transcription|transcription factor activity
miR-	NM_023071	FLJ13117	hypothetical protein	P + T
145			FLJ13117
miR-	AL561281	FLJ20373	hypothetical protein	M + P + T	ATP binding|cellular_component unknown|protein
145			FLJ20373		amino acid phosphorylation|protein kinase
					cascade|protein serine/threonine kinase
					activity|response to stress|signal transduction|small
					GTPase regulator activity|transferase activity
miR-	AK025444	FLJ21791	hypothetical protein	M + T
145			FLJ21791
miR-	NM_024713	FLJ22557	hypothetical protein	P + T
145			FLJ22557
miR-	AA872588	FLJ36155	likely ortholog of	P + T	DNA binding|negative regulation of transcription
145			mouse Gli-similar 1		from RNA polymerase II promoter|nucleus|positive
			Kruppel-like zinc finger		regulation of transcription from RNA polymerase II
			(Glis1)		promoter|regulation of transcription, DNA-
					dependent|specific RNA polymerase II transcription
					factor activity|transcription|zinc ion binding
miR-	AI434509	FLJ38499	Unnamed protein	P + T	nucleic acid binding
145			product [Homo
			sapiens], mRNA
			sequence
miR-	M62994	FLNB	filamin B, beta (actin	P + T	actin binding|actin binding|actin cytoskeleton|actin
145			binding protein 278)		cytoskeleton organization and biogenesis|cell
					differentiation|cytoskeletal anchoring|integral to
					plasma membrane|myogenesis|signal transduction
miR-	NM_002025	FMR2	fragile X mental	M + T	brain development|learning and/or memory
145			retardation 2
miR-	N29672	FOS	v-fos FBJ murine	M + T	proto-oncogene
145			osteosarcoma viral
			oncogene homolog
miR-	NM_002015	FOX01A	forkhead box O1A	M + P + T	anti-apoptosis|nucleus|regulation of transcription from
145			(rhabdomyosarcoma)		RNA polymerase II
					promoter|transcription|transcription factor activity
miR-	NM_003507	FZD7	frizzled homolog 7	M + P + T	G-protein coupled receptor activity|G-protein coupled
145			(Drosophila)		receptor protein signaling pathway|Wnt receptor
					activity|development|frizzled signaling
					pathway|integral to membrane|plasma membrane
miR-	AL049709	GGTL3	gamma-	M + P + T
145			glutamyltransferase-like 3
miR-	NM_022735	GOCAP1	golgi complex	M + P + T	Golgi apparatuslacyl-CoA binding|catalytic
145			associated protein 1,		activity|intracellular protein
			60 kDa		transport|membrane|mitochondrion|protein carrier
					activity|steroid biosynthesis
miR-	NM_020806	GPHN	gephyrin	P + T	Mo-molybdopterin cofactor biosynthesis|catalytic
145					activity|cytoskeleton
miR-	NM_015071	GRAF	GTPase regulator	P + T	Rho GTPase activator activitylactin cytoskeleton
145			associated with focal		organization and biogenesis|cellular_component
			adhesion kinase		unknown|neurogenesis
			pp125(FAK)
miR-	NM_017913	HARC	Hsp90-associating	P + T	cytokinesis|regulation of cell cycle
145			relative of Cdc37
miR-	BC006237	HECTD1	HECT domain	M + T	intracellular|ligase activity|receptor activity|ubiquitin
145			containing 1		cycle|ubiquitin-protein ligase activity
miR-	U64317	HEF1	enhancer of	P + T	actin filament bundle formation|cell
145			filamentation 1 (cas-like		adhesion|cytokinesis|cytoplasm|cytoskeleton|
			docking; Crk-associated		cytoskeleton organization and biogenesis|integrin-
			substrate related)		mediated signaling pathway|mitosis|nucleus|
					protein binding|regulation of cell cycle|regulation
					of cell growth|signal transduction|spindle
miR-	NM_016258	HGRG8	high-glucose-regulated	P + T
145			protein 8
miR-	AL162003	HIC2	hypermethylated in	P + T	DNA binding|negative regulation of transcription,
145			cancer 2		DNA-dependent|nucleus|protein C-terminus
					binding|transcription|zinc ion binding
miR-	NM_014212	HOXC11	homeo box C11	M + P + T	RNA polymerase II transcription factor
145					activity|development|endoderm
					development|nucleus|regulation of transcription,
					DNA-dependent|transcription factor activity
miR-	NM_002193	INHBB	inhibin, beta B (activin	M + P + T	cell differentiation|cytokine activity|defense
145			AB beta polypeptide)		response|extracellular region|growth|growth factor
					activity|hormone activity|host cell surface receptor
					binding|negative regulation of follicle-stimulating
					hormone secretion|negative regulation of hepatocyte
					growth factor biosynthesis|ovarian follicle
					development|positive regulation of follicle-
					stimulating hormone secretion|protein binding|protein
					homodimerization activity|response to external
					stimulus
miR-	NM_005544	IRS1	insulin receptor	M + P + T	cytoplasm|insulin receptor binding|protein
145			substrate 1		binding|signal transducer activity|signal
					transduction|transmembrane receptor protein tyrosine
					kinase docking protein activity
miR-	NM_006459	KEO4	similar to	P + T	catalytic activity
145			Caenorhabditis elegans
			protein C42C1.9
miR-	NM_014686	KIAA0355	KIAA0355 gene	P + T
145			product
miR-	NM_015176	KIAA0483	KIAA0483 protein	P + T	ubiquitin cycle
145
miR-	NM_014871	KIAA0710	KIAA0710 gene	M + P + T	cysteine-type endopeptidase activity|exonuclease
145			product		activity|nucleus|ubiquitin cycle|ubiquitin thiolesterase
					activity|ubiquitin-dependent protein catabolism
miR-	AA772278	KIAA1673	KIAA1673	M + P + T
145
miR-	AB051495	KIAA1708	KIAA1708 protein	P + T	ATP binding|microtubule associated
145					complex|microtubule motor activity|microtubule-
					based movement
miR-	AI814587	KIAA1715	KIAA1715 protein	M + T
145
miR-	AI187364	KIAA1894	KIAA1894 protein	P + T	integral to membrane
145
miR-	AF155117	KIF21A	kinesin family member	P + T	ATP binding|microtubule associated
145			21A		complex|microtubule motor activity|microtubule-
					based movement
miR-	NM_004235	KLF4	Kruppel-like factor 4	M + T	mesodermal cell fate determination|negative
145			(gut)		regulation of cell proliferation|negative regulation of
					transcription, DNA-dependent|negative regulation of
					transcription, DNA-dependent|nucleic acid
					binding|nucleus|transcription|transcription factor
					activity|transcription factor activity|transcriptional
					activator activity|transcriptional activator
					activity|transcriptional repressor
					activity|transcriptional repressor activity|zinc ion
					binding|zinc ion binding
miR-	T68150	LL5beta	hypothetical protein	M + T
145			FLJ21791
miR-	AI797833	LOC285148	a disintegrin and	P + T	catalytic activity
145			metalloproteinase
			domain 17 (tumor
			necrosis factor, alpha,
			converting enzyme)
miR-	NM_025146	MAK3P	likely ortholog of	P + T	N-acetyltransferase activity
145			mouse Mak3p homolog
			(S. cerevisiae)
miR-	BF971923	MAP3K3	mitogen-activated	M + P	ATP binding|MAP kinase kinase kinase
145			protein kinase kinase		activity|MAPKKK cascade|magnesium ion
			kinase 3		binding|positive regulation of I-kappaB kinase/NF-
					kappaB cascade|protein amino acid
					phosphorylation|protein kinase activity|protein
					serine/threonine kinase activity|signal transducer
					activity|transferase activity
miR-	NM_004834	MAP4K4	mitogen-activated	M + P + T	ATP binding|cellular_component unknown|protein
145			protein kinase kinase		amino acid phosphorylation|protein kinase
			kinase kinase 4		cascade|protein serine/threonine kinase
					activity|response to stress|signal transduction|small
					GTPase regulator activity|transferase activity
miR-	BF382281	MGC10120	Homo sapiens cDNA	P + T
145			FLJ30135 fis, clone
			BRACE2000061,
			mRNA sequence
miR-	BG231756	MGC10986	hypothetical protein	M + P	ATP binding|MAP kinase kinase kinase
145			MGC10986		activity|MAPKKK cascade|magnesium ion
					binding|positive regulation of I-kappaB kinase/NF-
					kappaB cascade|protein amino acid
					phosphorylation|protein kinase activity|protein
					serine/threonine kinase activity|signal transducer
					activity|transferase activity
miR-	BC004869	MGC2817	hypothetical protein	P + T	outer membrane|protein transport
145			MGC2817
miR-	BC002712	MYCN	v-myc	M + T	chromatin|nucleus|protein binding|regulation of
145			myelocytomatosis viral		transcription from RNA polymerase II
			related oncogene,		promoter|transcription factor activity
			neuroblastoma derived
			(avian)
miR-	AB007899	NEDD4L	neural precursor cell	P + T	excretion|intracellular|intracellular|ligase
145			expressed,		activity|positive regulation of endocytosis|protein
			developmentally down-		binding|protein ubiquitination|regulation of protein
			regulated 4-like		catabolism|response to metal ion|sodium channel
					regulator activity|sodium ion homeostasis|sodium ion
					transport|ubiquitin cycle|ubiquitin-protein ligase
					activity|ubiquitin-protein ligase activity|water
					homeostasis
miR-	NM_005863	NET1	neuroepithelial cell	P + T	guanyl-nucleotide exchange factor
145			transforming gene 1		activity|nucleus|regulation of cell growth|signal
					transduction
miR-	NM_003204	NFE2L1	nuclear factor	P + T	DNA binding|heme biosynthesis|inflammatory
145			(erythroid-derived 2)-		response|morphogenesis|nucleus|nucleus|regulation of
			like 1		transcription, DNA-
					dependent|transcription|transcription cofactor
					activity|transcription factor activity|transcription from
					RNA polymerase II promoter
miR-	NM_006469	NS1-BP	NS1-binding protein	M + P + T	RNA splicing|protein binding|response to
145					virus|spliceosome complex|transcription factor
					complex|transcription from RNA polymerase III
					promoter
miR-	NM_019094	NUDT4	nudix (nucleoside	P + T	calcium-mediated signaling|cyclic nucleotide
145			diphosphate linked		metabolism|cyclic-nucleotide-mediated
			moiety X)-type motif 4		signaling|diphosphoinositol-polyphosphate
					diphosphatase activity|hydrolase
					activity|intracellular|intracellular signaling
					cascade|intracellular transport|magnesium ion
					binding|regulation of RNA-nucleus export
miR-	AW149417	OAZ	OLF-1/EBF associated	P + T	nucleic acid binding|nucleus|zinc ion binding
145			zinc finger gene
miR-	NM_024586	OSBPL9	oxysterol binding	M + P	lipid transport|steroid metabolism
145			protein-like 9
miR-	AB040812	PAK7	p21(CDKN1A)-	M + T	ATP binding|protein amino acid
145			activated kinase 7		phosphorylation|protein serine/threonine kinase
					activity|transferase activity
miR-	NM_014456	PDCD4	programmed cell death	M + P + T	apoptosis
145			4 (neoplastic
			transformation
			inhibitor)
miR-	NM_002657	PLAGL2	pleiomorphic adenoma	M + P + T	nucleus|regulation of transcription, DNA-
145			gene-like 2		dependent|transcription|transcription factor
					activity|zinc ion binding
miR-	AK023546	PLCL2	phospholipase C-like 2	P + T	calcium ion binding|intracellular signaling
145					cascade|lipid metabolism|phosphoinositide
					phospholipase C activity
miR-	AI274352	PLN	phospholamban	P + T
145
miR-	NM_000944	PPP3CA	protein phosphatase 3	P + T	calcineurin complex|calcium ion binding|calmodulin
145			(formerly 2B), catalytic		binding|hydrolase activity|protein amino acid
			subunit, alpha isoform		dephosphorylation|protein serine/threonine
			(calcineurin A alpha)		phosphatase activity
miR-	BF247371	PRO1843	hypothetical protein	M + T
145			PRO1843
miR-	NM_000959	PTGFR	prostaglandin F receptor	P + T	G-protein coupled receptor protein signaling
145			(FP)		pathway|G-protein coupled receptor protein signaling
					pathway|integral to membrane|integral to plasma
					membrane|parturition|prostaglandin F receptor
					activity|prostaglandin F receptor activity|receptor
					activity|rhodopsin-like receptor activity|signal
					transduction|thromboxane receptor activity
miR-	NM_002890	RASA1	RAS p21 protein	P + T	Ras GTPase activator activity|intracellular signaling
145			activator (GTPase		cascade
			activating protein) 1
miR-	NM_006506	RASA2	RAS p21 protein	P + T	Ras GTPase activator activity|intracellular signaling
145			activator 2		cascade
miR-	NM_002912	REV3L	REV3-like, catalytic	M + P + T	3′-5′ exonuclease activity|DNA binding|DNA
145			subunit of DNA		repair|DNA replication|DNA-dependent DNA
			polymerase zeta (yeast)		replication|DNA-directed DNA polymerase
					activity|nucleotide binding|nucleus|transferase
					activity|zeta DNA polymerase activity|zeta DNA
					polymerase complex
miR-	NM_002924	RGS7	regulator of G-protein	P + T	heterotrimeric G-protein complex|intracellular
145			signalling 7		signaling cascade|regulation of G-protein coupled
					receptor protein signaling pathway|regulator of G-
					protein signaling activity|signal transducer activity
miR-	AL136924	RIN2	Ras and Rab interactor 2	P + T	GTPase activator activity|Rab guanyl-nucleotide
145					exchange factor activity|cellular_component
					unknown|endocytosis|intracellular signaling
					cascade|small GTPase mediated signal
					transduction|small GTPase regulator activity
miR-	BE463945	RTKN	rhotekin	P + T	intracellular|protein binding|signal transduction|signal
145					transduction
miR-	AF225986	SCN3A	sodium channel,	P + T	cation channel activity|cation transport|integral to
145			voltage-gated, type III,		membrane|membrane|sodium ion transport|voltage-
			alpha polypeptide		gated sodium channel activity|voltage-gated sodium
					channel complex
miR-	NM_006080	SEMA3A	sema domain,	P + T	cell differentiation|extracellular region|neurogenesis
145			immunoglobulin
			domain (Ig), short basic
			domain, secreted,
			(semaphorin) 3A
miR-	NM_020796	SEMA6A	sema domain,	P + T	apoptosis|axonlaxon guidance|cell differentiation|cell
145			transmembrane domain		surface receptor linked signal
			(TM), and cytoplasmic		transduction|cytoskeleton organization and
			domain, (semaphorin)		biogenesis|development|integral to
			6A		membrane|membrane|neurogenesis|protein
					binding|receptor activity
miR-	NM_004171	SLC1A2	solute carrier family 1	P + T	L-glutamate transport|L-glutamate transporter
145			(glial high affinity		activity|dicarboxylic acid transport|integral to
			glutamate transporter),		membrane|membrane|membrane
			member 2		fraction|sodium:dicarboxylate symporter
					activity|symporter activity|synaptic
					transmission|transport
miR-	NM_003759	SLC4A4	solute carrier family 4,	P + T	anion transport|inorganic anion exchanger
145			sodium bicarbonate		activity|integral to membrane|integral to plasma
			cotransporter, member 4		membrane|membrane|sodium:bicarbonate symporter
					activity|transport
miR-	NM_030918	SNX27	hypothetical protein	M + P + T	intracellular signaling cascade|protein binding|protein
145			My014		transport
miR-	AI360875	SOX11	SRY (sex determining	M + T	DNA binding|neurogenesis|nucleus|regulation of
145			region Y)-box 11		transcription, DNA-dependent|transcription
miR-	NM_000346	SOX9	SRY (sex determining	P + T	DNA binding|cartilage
145			region Y)-box 9		condensation|nucleus|regulation of transcription from
			(campomelic dysplasia,		RNA polymerase II promoter|skeletal
			autosomal sex-reversal)		development|specific RNA polymerase II
					transcription factor activity|transcription
miR-	AK023899	SRGAP1	SLIT-ROBO Rho	P + T	GTPase activator activity
145			GTPase activating
			protein 1
miR-	NM_003155	STC1	stanniocalcin 1	M + T	calcium ion homeostasis|cell surface receptor linked
145					signal transduction|cell-cell signaling|extracellular
					region|hormone activity|response to nutrients
miR-	BE219311	TIMM22	translocase of inner	M + P + T	integral to membrane|mitochondrial inner
145			mitochondrial		membrane|mitochondrion|protein transport|protein
			membrane 22 homolog		transporter activity
			(yeast)
miR-	AA705845	TLE4	transducin-like	M + P	frizzled signaling pathway|molecular_function
145			enhancer of split 4		unknown|nucleus|nucleus|regulation of
			(E(sp1) homolog,		transcription|regulation of transcription, DNA-
			Drosophila)		dependent
miR-	BC005016	TRIM2	tripartite motif-	P + T	cytoplasm|myosin binding|protein
145			containing 2		ubiquitination|ubiquitin ligase complex|ubiquitin-
					protein ligase activity|zinc ion binding
miR-	NM_025076	UXS1	UDP-glucuronate	M + P + T	carbohydrate metabolism|isomerase
145			decarboxylase 1		activity|nucleotide-sugar metabolism
miR-	NM_005433	YES1	v-yes-1 Yamaguchi	P + T	ATP binding|intracellular signaling cascade|protein
145			sarcoma viral oncogene		amino acid phosphorylation|protein-tyrosine kinase
			homolog 1		activity|transferase activity
miR-	BC003128	ZDHHC9	zinc finger, DHHC	P + T	integral to membrane|metal ion binding
145			domain containing 9
miR-	NM_019903	ADD3	adducin 3 (gamma)	P + T	calmodulin binding|cytoskeleton|membrane|structural
155					constituent of cytoskeleton
miR-	NM_020661	AICDA	activation-induced	P + T	B-cell differentiation|cellular_component
155			cytidine deaminase		unknown|cytidine deaminase activity|hydrolase
					activity|mRNA processing|zinc ion binding
miR-	NM_007202	AKAP10	A kinase (PRKA)	P + T	kinase activity|mitochondrion|protein binding|protein
155			anchor protein 10		localization|signal transducer activity|signal
					transduction
miR-	AI806395	ALFY	ALFY	P + T	binding|zinc ion binding
155
miR-	NM_000038	APC	adenomatosis polyposis	P + T	Wnt receptor signaling pathway|beta-catenin
155			coli		binding|cell adhesion|microtubule binding|negative
					regulation of cell cycle|protein complex
					assembly|signal transduction
miR-	NM_017610	ARK	Arkadia	P + T	protein ubiquitination|ubiquitin ligase
155					complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	BG032269	ARL8	ADP-ribosylation-like	M + P + T	GTP binding|small GTPase mediated signal
155			factor 8		transduction
miR-	AB000815	ARNTL	aryl hydrocarbon	P + T	circadian rhythm|nucleus|regulation of transcription,
155			receptor nuclear		DNA-dependent|signal transducer activity|signal
			translocator-like		transduction|transcription|transcription factor activity
miR-	NM_001670	ARVCF	armadillo repeat gene	P + T	cell adhesion|cytoskeleton|development|protein
155			deletes in		binding|structural molecule activity
			velocardiofacial
			syndrome
miR-	AK024064	ASTN2	astrotactin 2	P + T	integral to membrane
155
miR-	M95541	ATP2B1	ATPase, Ca++	M + P + T	ATP binding|calcium ion binding|calcium ion
155			transporting, plasma		transport|calcium-transporting ATPase
			membrane 1		activity|calmodulin binding|cation transport|hydrolase
					activity|hydrolase activity, acting on acid anhydrides,
					catalyzing transmembrane movement of
					substances|integral to plasma membrane|magnesium
					ion binding|membrane|metabolism
miR-	NM_001186	BACH1	BTB and CNC	P + T	DNA binding|nucleus|protein binding|regulation of
155			homology 1, basic		transcription, DNA-
			leucine zipper		dependent|transcription|transcription factor activity
			transcription factor 1
miR-	NM_007005	BCE-1	BCE-1 protein	P + T	frizzled signaling pathway|molecular_function
155					unknown|nucleus|nucleus|regulation of
					transcription|regulation of transcription, DNA-
					dependent
miR-	NM_022893	BCL11A	B-cell CLL/lymphoma	P + T	cytoplasm|hemopoiesis|nucleic acid
155			11A (zinc finger		binding|nucleus|nucleus|regulation of transcription,
			protein)		DNA-dependent|transcription|zinc ion binding
miR-	NM_001709	BDNF	brain-derived	M + T	growth factor activity|growth factor
155			neurotrophic factor		activity|neurogenesis
miR-	NM_014577	BRD1	bromodomain	P + T	DNA binding|cell cycle|nucleus|nucleus|regulation of
155			containing 1		transcription, DNA-dependent
miR-	NM_024529	C1orf28	chromosome 1 open	M + P + T
155			reading frame 28
miR-	NM_000719	CACNA1C	calcium channel,	P + T	calcium ion binding|calcium ion transport|cation
155			voltage-dependent, L		transport|integral to membrane|ion channel
			type, alpha 1C subunit		activity|ion transport|membrane|regulation of heart
					contraction rate|voltage-gated calcium channel
					activity|voltage-gated calcium channel
					activity|voltage-gated calcium channel
					complex|voltage-gated calcium channel complex
miR-	AL118798	CD47	CD47 antigen (Rh-	P + T	cell-matrix adhesion|integral to plasma
155			related antigen,		membrane|integrin-mediated signaling
			integrin-associated		pathway|plasma membrane|protein binding
			signal transducer)
miR-	AL564683	CEBPB	CCAAT/enhancer	M + P + T	acute-phase response|inflammatory
155			binding protein		response|nucleus|regulation of transcription, DNA-
			(C/EBP), beta		dependent|transcription|transcription factor
					activity|transcription from RNA polymerase II
					promoter
miR-	NM_007023	CGEF2	cAMP-regulated	M + P	3′,5′-cAMP binding|G-protein coupled receptor
155			guanine nucleotide		protein signaling pathway|cAMP-dependent protein
			exchange factor II		kinase complex|cAMP-dependent protein kinase
					regulator activity|exocytosis|guanyl-nucleotide
					exchange factor activity|membrane fraction|nucleotide
					binding|protein amino acid phosphorylation|small
					GTPase mediated signal transduction
miR-	AU152178	CMG2	capillary	P + T	integral to membrane|receptor activity
155			morphogenesis protein 2
miR-	NM_005776	CNIH	cornichon homolog	P + T	immune response|integral to membrane|intracellular
155			(Drosophila)		signaling cascade|membrane
miR-	AW241703	CNTN4	Homo sapiens cDNA	P + T	cell adhesion|membrane|protein binding
155			FLJ32716 fis, clone
			TESTI2000808, highly
			similar to Rattus
			norvegicus neural cell
			adhesion protein BIG-2
			precursor (BIG-2)
			mRNA, mRNA
			sequence
miR-	NM_000094	COL7A1	collagen, type VII,	P + T	basement membrane|cell adhesion|collagen type
155			alpha 1 (epidermolysis		VII|cytoplasm|epidermis development|phosphate
			bullosa, dystrophic,		transport|protein binding|serine-type endopeptidase
			dominant and recessive)		inhibitor activity|structural molecule activity
miR-	NM_003653	COPS3	COP9 constitutive	P + T	signalosome complex
155			photomorphogenic
			homolog subunit 3
			(Arabidopsis)
miR-	NM_005211	CSF1R	colony stimulating	M + P + T	ATP binding|antimicrobial humoral response (sensu
155			factor 1 receptor,		Vertebrata)|cell proliferation|development|integral to
			formerly McDonough		plasma membrane|macrophage colony stimulating
			feline sarcoma viral (v-		factor receptor activity|plasma membrane|protein
			fms) oncogene homolog		amino acid phosphorylation|receptor activity|signal
					transduction|transferase activity|transmembrane
					receptor protein tyrosine kinase signaling pathway
miR-	NM_001892	CSNK1A1	casein kinase 1, alpha 1	P + T	ATP binding|Wnt receptor signaling pathway|casein
155					kinase I activity|protein amino acid
					phosphorylation|protein amino acid
					phosphorylation|protein serine/threonine kinase
					activity|protein-tyrosine kinase activity|transferase
					activity
miR-	NM_005214	CTLA4	cytotoxic T-	P + T	immune response|immune response|integral to plasma
155			lymphocyte-associated		membrane|membrane
			protein 4
miR-	U69546	CUGBP2	CUG triplet repeat,	M + P + T	RNA binding|RNA binding|RNA
155			RNA binding protein 2		processing|neuromuscular junction
					development|nucleotide binding|regulation of heart
					contraction rate
miR-	NM_030927	DC-	tetraspanin similar to	P + T	integral to membrane
155		TM4F2	TM4SF9
miR-	NM_015652	DKFZP564P1916	DKFZP564P1916	P + T
155			protein
miR-	AF151831	DKFZP566C134	DKFZP566C134	P + T	protein binding
155			protein
miR-	NM_004411	DNCI1	dynein, cytoplasmic,	P + T	cytoplasmic dynein complex|motor activity
155			intermediate
			polypeptide 1
miR-	NM_001400	EDG1	endothelial	P + T	G-protein coupled receptor protein signaling
155			differentiation,		pathway|cell adhesion|integral to plasma
			sphingolipid G-protein-		membrane|lysosphingolipid and lysophosphatidic acid
			coupled receptor, 1		receptor activity|plasma membrane|receptor
					activity|signal transduction
miR-	NM_006795	EHD1	EH-domain containing 1	P + T	ATP binding|GTP binding|GTPase
155					activity|biological_process unknown|calcium ion
					binding|cellular_component unknown
miR-	NM_012081	ELL2	ELL-related RNA	M + P + T	RNA elongation from RNA polymerase II
155			polymerase II,		promoter|RNA polymerase II transcription factor
			elongation factor		activity|nucleus|regulation of transcription, DNA-
					dependent|transcription|transcription elongation factor
					complex
miR-	NM_005238	ETS1	v-ets erythroblastosis	P + T	RNA polymerase II transcription factor
155			virus E26 oncogene		activity|immune response|negative regulation of cell
			homolog 1 (avian)		proliferation|nucleus|regulation of transcription,
					DNA-dependent|transcription|transcription factor
					activity|transcription from RNA polymerase II
					promoter
miR-	NM_002009	FGF7	fibroblast growth factor	P + T	cell proliferation|cell-cell signaling|epidermis
155			7 (keratinocyte growth		development|extracellular region|growth factor
			factor)		activity|positive regulation of cell
					proliferation|regulation of cell cycle|response to
					wounding|signal transduction
miR-	NM_018208	FLJ10761	hypothetical protein	P + T	biological_process unknown|cellular_component
155			FLJ10761		unknown|choline kinase activity|transferase activity
miR-	NM_018243	FLJ10849	hypothetical protein	P + T	GTP binding|cell cycle|cytokinesis
155			FLJ10849
miR-	NM_022064	FLJ12565	hypothetical protein	P + T	ligase activity|protein ubiquitination|ubiquitin ligase
155			FLJ12565		complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-	NM_018391	FLJ23277	FLJ23277 protein	P + T
155
miR-	NM_021078	GCN5L2	GCN5 general control	M + P + T	N-acetyltransferase activity|chromatin
155			of amino-acid synthesis		remodeling|histone acetyltransferase activity|histone
			5-like 2 (yeast)		deacetylase binding|nucleus|protein amino acid
					acetylation|regulation of transcription from RNA
					polymerase II promoter|transcription|transcription
					coactivator activity|transferase activity
miR-	NM_018178	GPP34R	hypothetical protein	P + T
155			FLJ10687
miR-	AF019214	HBP1	HMG-box containing	M + P	DNA binding|nucleus|regulation of transcription,
155			protein 1		DNA-dependent
miR-	NM_006037	HDAC4	histone deacetylase 4	P + T	B-cell differentiation|cell cycle|chromatin
155					modification|cytoplasm|development|histone
					deacetylase activity|histone deacetylase
					complex|hydrolase activity|inflammatory
					response|negative regulation of
					myogenesis|neurogenesis|nucleus|regulation of
					transcription, DNA-
					dependent|transcription|transcription factor
					binding|transcriptional repressor activity
miR-	NM_001530	HIF1A	hypoxia-inducible	P + T	RNA polymerase II transcription factor activity,
155			factor 1, alpha subunit		enhancer binding|electron transport|histone
			(basic helix-loop-helix		acetyltransferase
			transcription factor)		binding|homeostasis|nucleus|nucleus|protein
					heterodimerization activity|protein heterodimerization
					activity|regulation of transcription, DNA-
					dependent|response to hypoxia|signal transducer
					activity|signal transduction|signal
					transduction|transcription factor activity
miR-	AL023584	HIVEP2	human	P + T
155			immunodeficiency virus
			type I enhancer binding
			protein 2
miR-	AI682088	HLCS	holocarboxylase	P + T	biotin-[acetyl-CoA-carboxylase] ligase activity|biotin-
155			synthetase (biotin-		[methylcrotonoyl-CoA-carboxylase] ligase
			[proprionyl-Coenzyme		activity|biotin-[methylmalonyl-CoA-
			A-carboxylase (ATP-		carboxytransferase] ligase activity|biotin-[propionyl-
			hydrolysing)] ligase)		CoA-carboxylase (ATP-hydrolyzing)] ligase
					activity|ligase activity|protein modification
miR-	NM_020190	HNOEL-	HNOEL-iso protein	P + T
155		iso
miR-	NM_014002	IKBKE	inhibitor of kappa light	P + T	ATP binding|NF-kappaB-inducing kinase
155			polypeptide gene		activity|cytoplasm|immune response|positive
			enhancer in B-cells,		regulation of I-kappaB kinase/NF-kappaB
			kinase epsilon		cascade|protein amino acid phosphorylation|protein
					serine/threonine kinase activity|signal transducer
					activity|transferase activity
miR-	D13720	ITK	IL2-inducible T-cell	P + T	ATP binding|cellular defense response|intracellular
155			kinase		signaling cascade|non-membrane spanning protein
					tyrosine kinase activity|protein amino acid
					phosphorylation|transferase activity
miR-	NM_002249	KCNN3	potassium	P + T	calcium-activated potassium channel activity|calcium-
155			intermediate/small		activated potassium channel activity|calmodulin
			conductance calcium-		binding|integral to membrane|ion channel activity|ion
			activated channel,		transport|membrane|membrane
			subfamily N, member 3		fraction|neurogenesis|potassium ion
					transport|potassium ion transport|small conductance
					calcium-activated potassium channel activity|synaptic
					transmission|voltage-gated potassium channel
					complex
miR-	AB033100	KIAA1274	KIAA protein (similar	P + T	protein tyrosine phosphatase activity
155			to mouse paladin)
miR-	NM_017780	KIAA1416	KIAA1416 protein	P + T	ATP binding|chromatin|chromatin assembly or
155					disassembly|chromatin binding|helicase
					activity|nucleus
miR-	NM_002264	KPNA1	karyopherin alpha 1	P + T	NLS-bearing substrate-nucleus
155			(importin alpha 5)		import|cytoplasm|intracellular protein
					transport|nuclear localization sequence
					binding|nuclear pore|nucleus|protein binding|protein
					transporter activity|regulation of DNA recombination
miR-	AK021602	KPNA4	karyopherin alpha 4	P + T	NLS-bearing substrate-nucleus
155			(importin alpha 3)		import|binding|intracellular protein
					transport|nucleus|protein transporter activity
miR-	NM_020354	LALP1	lysosomal apyrase-like	M + P + T	hydrolase activity
155			protein 1
miR-	AW242408	LOC151531	Similar to uridine	M + P + T	cytosol|nucleoside metabolism|nucleotide
155			phosphorylase [Homo		catabolism|protein binding|transferase activity,
			sapiens], mRNA		transferring glycosyl groups|type III intermediate
			sequence		filament|uridine metabolism|uridine phosphorylase
					activity
miR-	NM_016210	LOC51161	g20 protein	P + T
155
miR-	NM_018557	LRP1B	low density lipoprotein-	P + T	calcium ion binding|integral to membrane|low-density
155			related protein 1B		lipoprotein receptor activity|membrane|protein
			(deleted in tumors)		transport|receptor activity|receptor mediated
					endocytosis
miR-	NM_002446	MAP3K10	mitogen-activated	M + P + T	ATP binding|JUN kinase kinase kinase
155			protein kinase kinase		activity|activation of
			kinase 10		JNK|autophosphorylation|induction of
					apoptosis|protein homodimerization activity|protein
					serine/threonine kinase activity|protein-tyrosine
					kinase activity|signal transduction|transferase activity
miR-	NM_003954	MAP3K14	mitogen-activated	P + T	ATP binding|protein amino acid
155			protein kinase kinase		phosphorylation|protein serine/threonine kinase
			kinase 14		activity|transferase activity
miR-	AL117407	MAP3K7IP2	mitogen-activated	P + T	kinase activity|positive regulation of I-kappaB
155			protein kinase kinase		kinase/NF-kappaB cascade|positive regulation of I-
			kinase 7 interacting		kappaB kinase/NF-kappaB cascade|signal transducer
			protein 2		activity|signal transducer activity
miR-	NM_004992	MECP2	methyl CpG binding	M + P + T	DNA binding|negative regulation of transcription
155			protein 2 (Rett		from RNA polymerase II promoter|nucleus|regulation
			syndrome)		of transcription, DNA-
					dependent|transcription|transcription corepressor
					activity
miR-	NM_002398	MEIS1	Meis1, myeloid	M + P + T	RNA polymerase II transcription factor
155			ecotropic viral		activity|nucleus|regulation of transcription, DNA-
			integration site 1		dependent|transcription factor activity
			homolog (mouse)
miR-	NM_016289	MO25	MO25 protein	P + T
155
miR-	AA621962	MYO1D	myosin ID	M + P + T	ATP bindinglactin binding|calmodulin binding|motor
155					activity|myosin
miR-	NM_030571	N4WBP5	likely ortholog of	P + T	positive regulation of I-kappaB kinase/NF-kappaB
155			mouse Nedd4 WW		cascade|signal transducer activity
			binding protein 5
miR-	NM_014903	NAV3	neuron navigator 3	P + T	ATP binding|mitochondrion|nucleoside-
155					triphosphatase activity|nucleotide binding
miR-	NM_030571	NDFIP1	likely ortholog of	P + T	positive regulation of I-kappaB kinase/NF-kappaB
155			mouse Nedd4 WW		cascade|signal transducer activity
			binding protein 5
miR-	NM_006599	NFAT5	nuclear factor of	M + P + T	RNA polymerase II transcription factor
155			activated T-cells 5,		activity|excretion|nucleus|regulation of transcription,
			tonicity-responsive		DNA-dependent|signal transduction|transcription
					factor activity|transcription from RNA polymerase II
					promoter
miR-	NM_002515	NOVA1	neuro-oncological	M + P + T	RNA binding|RNA binding|RNA splicing|RNA
155			ventral antigen 1		splicing|locomotory behavior|locomotory
					behavior|nucleus|synaptic transmission|synaptic
					transmission
miR-	AI373299	PANK1	pantothenate kinase 1	P + T	ATP binding|coenzyme A biosynthesis|pantothenate
155					kinase activity|transferase activity
miR-	BG110231	PAPOLA	poly(A) polymerase	P + T	RNA binding|cytoplasm|mRNA
155			alpha		polyadenylylation|mRNA
					processing|nucleus|polynucleotide adenylyltransferase
					activity|transcription|transferase activity
miR-	NM_020403	PCDH9	protocadherin 9	M + P + T	calcium ion binding|cell adhesion|homophilic cell
155					adhesion|integral to membrane|membrane|protein
					binding
miR-	NM_002655	PLAG1	pleiomorphic adenoma	P + T	nucleic acid binding|nucleus|transcription factor
155			gene 1		activity|zinc ion binding
miR-	AJ272212	PSKH1	protein serine kinase H1	P + T	ATP binding|Golgi apparatus|nucleus|protein amino
155					acid phosphorylation|protein serine/threonine kinase
					activity|transferase activity
miR-	NM_014904	Rab11-	KIAA0941 protein	P + T
155		FIP2
miR-	AF322067	RAB34	RAB34, member RAS	P + T	GTP binding|Golgi apparatus|protein transport|small
155			oncogene family		GTPase mediated signal transduction
miR-	NM_002869	RAB6A	RAB6A, member RAS	M + P + T	GTP binding|GTPase activity|Golgi apparatus|protein
155			oncogene family		transport|small GTPase mediated signal transduction
miR-	AL136727	RAB6C	RAB6C, member RAS	M + P + T	GTP binding|GTPase activity|intracellular|protein
155			oncogene family		transport|response to drug|small GTPase mediated
					signal transduction
miR-	NM_002902	RCN2	reticulocalbin 2, EF-	P + T	calcium ion binding|endoplasmic reticulum|protein
155			hand calcium binding		binding
			domain
miR-	AJ223321	RP58	zinc finger protein 238	M + P + T
155
miR-	NM_002968	SALL1	sal-like 1 (Drosophila)	P + T	morphogenesis|nucleus|regulation of transcription,
155					DNA-dependent|transcription|transcription factor
					activity|zinc ion binding
miR-	NM_002971	SATB1	special AT-rich	P + T	double-stranded DNA binding|establishment and/or
155			sequence binding		maintenance of chromatin
			protein 1 (binds to		architecture|nucleus|regulation of transcription, DNA-
			nuclear matrix/scaffold-		dependent|transcription factor activity
			associating DNA's)
miR-	NM_003469	SCG2	secretogranin II	P + T	calcium ion binding|protein secretion
155			(chromogranin C)
miR-	NM_005625	SDCBP	syndecan binding	P + T	actin cytoskeleton organization and
155			protein (syntenin)		biogenesis|adherens junction|cytoskeletal adaptor
					activity|cytoskeleton|endoplasmic
					reticulum|interleukin-5 receptor binding|interleukin-5
					receptor complex|intracellular signaling
					cascade|metabolism|neurexin
					binding|nucleus|oxidoreductase activity|plasma
					membrane|protein binding|protein heterodimerization
					activity|protein-membrane targeting|substrate-bound
					cell migration, cell extension|synaptic
					transmission|syndecan binding
miR-	NM_000232	SGCB	sarcoglycan, beta	P + T	cytoskeleton|cytoskeleton organization and
155			(43 kDa dystrophin-		biogenesis|integral to plasma membrane|muscle
			associated glycoprotein)		development|sarcoglycan complex
miR-	NM_013257	SGKL	serum/glucocorticoid	P + T	ATP binding|intracellular signaling cascade|protein
155			regulated kinase-like		amino acid phosphorylation|protein amino acid
					phosphorylation|protein serine/threonine kinase
					activity|protein serine/threonine kinase
					activity|protein-tyrosine kinase activity|response to
					stress|transferase activity
miR-	NM_005069	SIM2	single-minded homolog	P + T	cell differentiation|neurogenesis|nucleus|regulation of
155			2 (Drosophila)		transcription, DNA-dependent|signal transducer
					activity|signal transduction|transcription|transcription
					factor activity
miR-	AA927480	SKI	v-ski sarcoma viral	P + T
155			oncogene homolog
			(avian)
miR-	NM_006748	SLA	Src-like-adaptor	P + T	SH3/SH2 adaptor activity|intracellular signaling
155					cascade
miR-	AI684141	SMARCA4	SWI/SNF related,	P + T	ATP binding|DNA binding|helicase activity|helicase
155			matrix associated, actin		activity|hydrolase
			dependent regulator of		activity|nucleoplasm|nucleus|regulation of
			chromatin, subfamily a,		transcription from RNA polymerase II
			member 4		promoter|transcription|transcription coactivator
					activity|transcription factor activity
miR-	AB005043	SOCS1	suppressor of cytokine	M + P + T	JAK-STAT cascade|cytoplasm|insulin-like growth
155			signaling 1		factor receptor binding|intracellular signaling
					cascade|negative regulation of JAK-STAT
					cascade|protein kinase binding|protein kinase inhibitor
					activity|regulation of cell growth|ubiquitin cycle
miR-	NM_004232	SOCS4	suppressor of cytokine	M + P	JAK-STAT cascade|cytoplasm|defense
155			signaling 4		response|intracellular signaling cascade|regulation of
					cell growth
miR-	NM_005986	SOX1	SRY (sex determining	P + T	DNA binding|establishment and/or maintenance of
155			region Y)-box 1		chromatin architecture|nucleus|regulation of
					transcription, DNA-dependent|regulation of
					transcription, DNA-dependent|transcription factor
					activity
miR-	AI360875	SOX11	SRY (sex determining	M + T	DNA binding|neurogenesis|nucleus|regulation of
155			region Y)-box 11		transcription, DNA-dependent|transcription
miR-	AL136780	SOX6	SRY (sex determining	P + T	establishment and/or maintenance of chromatin
155			region Y)-box 6		architecture|heart development|muscle
					development|nucleus|regulation of transcription,
					DNA-dependent|transcription|transcription factor
					activity
miR-	AW470841	SP3	Sp3 transcription factor	P + T	DNA binding|nucleus|regulation of transcription,
155					DNA-dependent|transcription|transcriptional activator
					activity|transcriptional repressor activity|zinc ion
					binding
miR-	BF224259	SPF30	splicing factor 30,	P + T	RNA splicing|RNA splicing factor activity,
155			survival of motor		transesterification
			neuron-related		mechanism|apoptosis|cytoplasm|induction of
					apoptosis|spliceosome assembly|spliceosome complex
miR-	NM_003120	SPI1	spleen focus forming	M + T	negative regulation of transcription from RNA
155			virus (SFFV) proviral		polymerase II promoter|nucleus|regulation of
			integration oncogene		transcription, DNA-
			spi1		dependent|transcription|transcription factor activity
miR-	BE676214	SSH2	slingshot 2	P + T	protein amino acid dephosphorylation|protein
155					tyrosine/serine/threonine phosphatase activity
miR-	AF159447	SUFU	suppressor of fused	P + T	cell cycle|cytoplasm|development|negative regulation
155			homolog (Drosophila)		of cell cycle|nucleus|proteolysis and
					peptidolysis|signal transducer activity|signal
					transduction|skeletal development|transcription
					corepressor activity
miR-	NM_006754	SYPL	synaptophysin-like	M + P + T	integral to plasma membrane|membrane|synaptic
155			protein		transmission|synaptic vesicle|transport|transporter
					activity
miR-	NM_006286	TFDP2	transcription factor Dp-	P + T	DNA metabolism|nucleus|regulation of cell
155			2 (E2F dimerization		cycle|regulation of transcription from RNA
			partner 2)		polymerase II promoter|transcription|transcription
					cofactor activity|transcription factor
					activity|transcription factor complex
miR-	AA705845	TLE4	transducin-like	P + T	frizzled signaling pathway|molecular_function
155			enhancer of split 4		unknown|nucleus|nucleus|regulation of
			(E(sp1) homolog,		transcription|regulation of transcription, DNA-
			Drosophila)		dependent
miR-	NM_014765	TOMM20	translocase of outer	P + T	integral to membrane|mitochondrial outer membrane
155			mitochondrial		translocase complex|mitochondrion|outer
			membrane 20 (yeast)		membrane|protein translocase activity|protein-
			homolog		mitochondrial targeting
miR-	AW341649	TP53INP1	tumor protein p53	P + T	apoptosis|nucleus
155			inducible nuclear
			protein 1
miR-	BC005016	TRIM2	tripartite motif-	P + T	cytoplasm|myosin binding|protein
155			containing 2		ubiquitination|ubiquitin ligase complex|ubiquitin-
					protein ligase activity|zinc ion binding
miR-	AA524505	TSGA	zinc finger protein	P + T	nucleus
155
miR-	AW157525	TSGA14	testis specific, 14	M + P + T	centrosome
155
miR-	X62048	WEE1	WEE1 homolog (S. pombe)	P + T	ATP binding|cytokinesis|mitosis|nucleus|protein
155					amino acid phosphorylation|protein serine/threonine
					kinase activity|protein-tyrosine kinase
					activity|regulation of cell cycle|transferase activity
miR-	AC005539	WUGSC:H_NH0335J18.1	Similar to uridine	M + P + T
155			phosphorylase [Homo
			sapiens], mRNA
			sequence
miR-	NM_003413	ZIC3	Zic family member 3	P + T	DNA binding|determination of left/right
155			heterotaxy 1 (odd-		symmetry|nucleus|regulation of transcription, DNA-
			paired homolog,		dependent|transcription|zinc ion binding
			Drosophila)
miR-	NM_007345	ZNF236	zinc finger protein 236	P + T	nucleus|regulation of transcription, DNA-
155					dependent|transcription|transcription factor
					activity|zinc ion binding
miR-	NM_006352	ZNF238	zinc finger protein 238	M + P + T	chromosome organization and biogenesis (sensu
155					Eukaryota)|negative regulation of transcription from
					RNA polymerase II promoter|nuclear
					chromosome|nucleic acid binding|nucleus|protein
					binding|protein binding|regulation of transcription,
					DNA-dependent|specific RNA polymerase II
					transcription factor activity|transcription|transcription
					factor activity|transport|zinc ion binding
miR-21	NM_005164	ABCD2	ATP-binding cassette,	M + P	ATP binding|ATP-binding cassette (ABC) transporter
			sub-family D (ALD),		complex|ATPase activity|ATPase activity, coupled to
			member 2		transmembrane movement of substances|fatty acid
					metabolism|integral to plasma
					membrane|membrane|peroxisome|transport
miR-21	NM_001616	ACVR2	activin A receptor, type	P + T	ATP binding|integral to plasma
			II		membrane|membrane|protein amino acid
					phosphorylation|receptor activity|transferase
					activity|transforming growth factor beta receptor
					activity|transmembrane receptor protein
					serine/threonine kinase signaling pathway
miR-21	NM_015339	ADNP	activity-dependent	P + T	nucleus|regulation of transcription, DNA-
			neuroprotector		dependent|transcription factor activity|zinc ion
					binding
miR-21	AI990366	ARHGEF7	Rho guanine nucleotide	P + T	guanyl-nucleotide exchange factor activity|signal
			exchange factor (GEF) 7		transduction
miR-21	NM_017610	ARK	Arkadia	P + T	protein ubiquitination|ubiquitin ligase
					complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-21	NM_014034	ASF1A	DKFZP547E2110	P + T	chromatin binding|loss of chromatin silencing|nucleus
			protein
miR-21	NM_017680	ASPN	asporin (LRR class 1)	P + T
miR-21	NM_000657	BCL2	B-cell CLL/lymphoma 2	P + T	anti-apoptosis|endoplasmic reticulum|humoral
					immune response|integral to
					membrane|membrane|mitochondrial outer
					membrane|mitochondrial outer
					membrane|mitochondrion|negative regulation of cell
					proliferation|nucleus|protein binding|regulation of
					apoptosis|regulation of cell cycle|release of
					cytochrome c from mitochondria
miR-21	NM_014577	BRD1	bromodomain	P + T	DNA binding|cell cycle|nucleus|nucleus|regulation of
			containing 1		transcription, DNA-dependent
miR-21	AA902767	BRD2	bromodomain	P + T	nucleus|protein serine/threonine kinase
			containing 2		activity|spermatogenesis
miR-21	NM_014962	BTBD3	BTB (POZ) domain	P + T	protein binding
			containing 3
miR-21	NM_006763	BTG2	BTG family, member 2	P + T	DNA repair|negative regulation of cell
					proliferation|regulation of transcription, DNA-
					dependent|transcription|transcription factor activity
miR-21	AK025768	C20orf99	chromosome 20 open	P + T	nucleic acid binding
		reading frame 99
miR-21	AI671238	CAPN3	Homo sapiens cDNA	P + T	calcium ion binding|calpain activity|calpain
			FLJ23750 fis, clone		activity|intracellular|intracellular|muscle
			HEP16527, mRNA		development|proteolysis and peptidolysis|proteolysis
			sequence		and peptidolysis|signal transducer activity
miR-21	NM_002981	CCL1	chemokine (C-C motif)	P + T	calcium ion homeostasis|cell-cell signaling|chemokine
			ligand 1		activity|chemotaxis|extracellular space|inflammatory
					response|sensory perception|signal transduction|viral
					life cycle
miR-21	BF939071	CCM1	cerebral cavernous	M + P	binding|catalytic activity|cytoskeleton|small GTPase
			malformations 1		mediated signal transduction|small GTPase regulator
					activity
miR-21	NM_001789	CDC25A	cell division cycle 25A	AP + T	cell proliferation|cytokinesis|hydrolase
					activity|intracellular|mitosis|protein amino acid
					dephosphorylation|protein tyrosine phosphatase
					activity|regulation of cyclin dependent protein kinase
					activity
miR-21	NM_001842	CNTFR	ciliary neurotrophic	M + P + T	ciliary neurotrophic factor receptor activity|cytokine
			factor receptor		binding|extrinsic to membrane|neurogenesis|receptor
					activity|signal transduction
miR-21	NM_001310	CREBL2	cAMP responsive	P + T	nucleus|regulation of transcription, DNA-
			element binding		dependent|signal
			protein-like 2		transduction|transcription|transcription factor activity
miR-21	NM_016441	CRIM1	cysteine-rich motor	M + P + T	insulin-like growth factor receptor activity|integral to
			neuron 1		membrane|membrane fraction|neurogenesis|serine-
					type endopeptidase inhibitor activity
miR-21	NM_015396	DKFZP434A043	DKFZP434A043	P + T	cell adhesion|cytoskeleton|mitotic chromosome
			protein		condensation|protein binding|structural molecule
					activity
miR-21	AL047650	DKFZp434A2417	endozepine-related	P + T	acyl-CoA binding
			protein precursor
miR-21	AB028628	DKFZP547E2110	DKFZP547E2110	P + T	chromatin binding|loss of chromatin silencing|nucleus
			protein
miR-21	NM_031305	DKFZP564B1162	hypothetical protein	P + T	GTPase activator activity
			DKFZp564B1162
miR-21	NM_004405	DLX2	distal-less homeo box 2	P + T	brain development|development|nucleus|regulation of
					transcription, DNA-dependent|transcription factor
					activity
miR-21	NM_001949	E2F3	E2F transcription factor 3	M + P + T	nucleus|protein binding|regulation of cell
					cycle|regulation of transcription, DNA-
					dependent|transcription|transcription factor
					activity|transcription factor complex|transcription
					initiation from RNA polymerase II promoter
miR-21	NM_006795	EHD1	EH-domain containing 1	P + T	ATP binding|GTP binding|GTPase
					activity|biological_process unknown|calcium ion
					binding|cellular_component unknown
miR-21	NM_001412	EIF1A	eukaryotic translation	P + T	RNA binding|eukaryotic translation initiation factor
			initiation factor 1A		4F complex|protein biosynthesis|translation initiation
					factor activity|translational initiation|translational
					initiation
miR-21	AI832074	EIF2C2	eukaryotic translation	P + T	cellular_component unknown|protein
			initiation factor 2C, 2		biosynthesis|translation initiation factor activity
miR-21	NM_006874	ELF2	E74-like factor 2 (ets	P + T	nucleus|nucleus|protein binding|protein
			domain transcription		binding|regulation of transcription from RNA
			factor)		polymerase II promoter|regulation of transcription,
					DNA-dependent|transcription factor
					activity|transcriptional activator
					activity|transcriptional activator activity
miR-21	NM_004438	EPHA4	EphA4	P + T	ATP binding|ephrin receptor activity|integral to
					plasma membrane|membrane|protein amino acid
					phosphorylation|receptor activity|signal
					transduction|transferase activity|transmembrane
					receptor protein tyrosine kinase signaling pathway
miR-21	BE888593	FLJ11220	hypothetical protein	P + T
			FLJ11220
miR-21	NM_017637	FLJ20043	hypothetical protein	P + T	nucleic acid binding|nucleus|zinc ion binding
			FLJ20043
miR-21	AF019214	HBP1	HMG-box containing	M + P + T	DNA binding|nucleus|regulation of transcription,
			protein 1		DNA-dependent
miR-21	NM_000214	JAG1	jagged 1 (Alagille	M + P + T	Notch binding|Notch signaling
			syndrome)		pathway|angiogenesis|calcium ion binding|calcium
					ion binding|cell communication|cell fate
					determination|development|endothelial cell
					differentiation|extracellular region|growth factor
					activity|hemopoiesis|integral to plasma
					membrane|keratinocyte
					differentiation|membrane|myoblast
					differentiation|neurogenesis|regulation of cell
					migration|regulation of cell proliferation|structural
					molecule activity
miR-21	NM_002232	KCNA3	potassium voltage-gated	M + P + T	cation transport|delayed rectifier potassium channel
			channel, shaker-related		activity|integral to membrane|membrane|membrane
			subfamily, member 3		fraction|potassium ion transport|voltage-gated
					potassium channel complex
miR-21	NM_014766	KIAA0193	KIAA0193 gene	P + T	cellular_component unknown|dipeptidase
			product		activity|exocytosis|proteolysis and peptidolysis
miR-21	NM_014912	KIAA0940	KIAA0940 protein	M + P + T	nucleic acid binding
miR-21	NM_014952	KIAA0945	KIAA0945 protein	P + T	DNA binding
miR-21	NM_017780	KIAA1416	KIAA1416 protein	P + T	ATP binding|chromatin|chromatin assembly or
					disassembly|chromatin binding|helicase
					activity|nucleus
miR-21	AB040901	KIAA1468	KIAA1468 protein	P + T	binding|mitotic chromosome condensation
miR-21	U90268	Krit1	cerebral cavernous	M + P	binding|catalytic activity|cytoskeleton|small GTPase
			malformations 1		mediated signal transduction|small GTPase regulator
					activity
miR-21	BF591611	LOC147632	hypothetical protein	P + T	oxidoreductase activity|zinc ion binding
			BC010734
miR-21	NM_005904	MADH7	MAD, mothers against	P + T	intracellular|protein binding|receptor signaling protein
			decapentaplegic		serine/threonine kinase signaling protein
			homolog 7 (Drosophila)		activity|regulation of transcription, DNA-
					dependent|response to
					stress|transcription|transforming growth factor beta
					receptor signaling pathway|transforming growth
					factor beta receptor, inhibitory cytoplasmic mediator
					activity
miR-21	NM_025146	MAK3P	likely ortholog of	P + T	N-acetyltransferase activity
			mouse Mak3p homolog
			(S. cerevisiae)
miR-21	NM_014319	MAN1	integral inner nuclear	P + T	integral to membrane|integral to nuclear inner
			membrane protein		membrane|membrane fraction|nuclear
					membrane|nucleotide binding
miR-21	AW025150	MAP3K12	mitogen-activated	M + T	ATP binding|JNK cascade|cytoplasm|magnesium ion
			protein kinase kinase		binding|plasma membrane|protein amino acid
			kinase 12		phosphorylation|protein kinase cascade|protein
					serine/threonine kinase activity|protein-tyrosine
					kinase activity|transferase activity
miR-21	NM_012325	MAPRE1	microtubule-associated	P + T	cell proliferation|cytokinesis|microtubule
			protein, RP/EB family,		binding|mitosis|protein C-terminus binding|regulation
			member 1		of cell cycle
miR-21	NM_002380	MATN2	matrilin 2	P + T	biological_process unknown|calcium ion
					binding|extracellular matrix (sensu Metazoa)
miR-21	NM_018834	MATR3	matrin 3	M + P + T	RNA binding|nuclear inner membrane|nucleotide
					binding|nucleus|structural molecule activity|zinc ion
					binding
miR-21	NM_021038	MBNL1	muscleblind-like	M + P + T	cytoplasm|double-stranded RNA binding|embryonic
			(Drosophila)		development (sensu Mammalia)|embryonic limb
					morphogenesis|muscle development|myoblast
					differentiation|neurogenesis|nucleic acid
					binding|nucleus|nucleus
miR-21	AI139252	MGC16063	ribosomal protein L35a	P + T	JAK-STAT cascadelacute-phase response|calcium ion
					binding|cell
					motility|cytoplasm|hematopoietin/interferon-class
					(D200-domain) cytokine receptor signal transducer
					activity|intracellular signaling cascade|negative
					regulation of transcription from RNA polymerase II
					promoter|neurogenesis|nucleus|nucleus|regulation of
					transcription, DNA-dependent|signal transducer
					activity|transcription|transcription factor
					activity|transcription factor activity
miR-21	BC004162	MGC2452	hypothetical protein	P + T	fatty acid metabolism|generation of precursor
			MGC2452		metabolites and energy|ligand-dependent nuclear
					receptor activity|lipid
					metabolism|nucleus|nucleus|regulation of
					transcription, DNA-dependent|steroid hormone
					receptor activity|transcription|transcription factor
					activity|transcription factor activity|transcription from
					RNA polymerase II promoter
miR-21	NM_024052	MGC3048	hypothetical protein	P + T
			MGC3048
miR-21	AB049636	MRPL9	mitochondrial	P + T	mitochondrion|protein
			ribosomal protein L9		biosynthesis|ribosome|structural constituent of
					ribosome
miR-21	NM_015678	NBEA	neurobeachin	P + T	Golgi trans face|cytosol|endomembrane
					system|plasma membrane|post-Golgi
					transport|postsynaptic membrane|protein kinase A
					binding
miR-21	AI700518	NFIB	nuclear factor I/B	M + T	DNA replication|nucleus|nucleus|regulation of
					transcription, DNA-
					dependent|transcription|transcription factor
					activity|transcription factor activity
miR-21	NM_002527	NTF3	neurotrophin 3	M + P	anti-apoptosis|cell motility|cell-cell signaling|growth
					factor activity|neurogenesis|signal transduction
miR-21	U24223	PCBP1	poly(rC) binding	M + P + T	RNA binding|catalytic activity|cytoplasm|mRNA
			protein 1		metabolism|nucleus|ribonucleoprotein
					complex|single-stranded DNA binding
miR-21	NM_005016	PCBP2	poly(rC) binding	M + T	DNA binding|RNA binding|cytoplasm|mRNA
			protein 2		metabolism|nucleic acid
					binding|nucleus|ribonucleoprotein complex
miR-21	NM_014456	PDCD4	programmed cell death	P + T	apoptosis
			4 (neoplastic
			transformation
			inhibitor)
miR-21	AF338650	PDZD2	PDZ domain containing 2	P + T
miR-21	NM_000325	PITX2	paired-like	M + P + T	determination of left/right
			homeodomain		symmetry|development|nucleus|organogenesis|
			transcription factor 2		regulation of transcription, DNA-dependent|
					transcription factor activity
miR-21	NM_002655	PLAG1	pleiomorphic adenoma	P + T	nucleic acid binding|nucleus|transcription factor
			gene 1		activity|zinc ion binding
miR-21	NM_005036	PPARA	peroxisome	P + T	fatty acid metabolism|generation of precursor
			proliferative activated		metabolites and energy|ligand-dependent nuclear
			receptor, alpha		receptor activity|lipid
					metabolism|nucleus|nucleus|regulation of
					transcription, DNA-dependent|steroid hormone
					receptor activity|transcription|transcription factor
					activity|transcription factor activity|transcription from
					RNA polymerase II promoter
miR-21	NM_002711	PPP1R3A	protein phosphatase 1,	P + T	carbohydrate metabolism|glycogen
			regulatory (inhibitor)		metabolism|hydrolase activity|integral to
			subunit 3A (glycogen		membrane|phosphoprotein phosphatase activity|type 1
			and sarcoplasmic		serine/threonine specific protein phosphatase inhibitor
			reticulum binding		activity
			subunit, skeletal
			muscle)
miR-21	NM_000944	PPP3CA	protein phosphatase 3	P + T	calcineurin complex|calcium ion binding|calmodulin
			(formerly 2B), catalytic		binding|hydrolase activity|protein amino acid
			subunit, alpha isoform		dephosphorylation|protein serine/threonine
			(calcineurin A alpha)		phosphatase activity
miR-21	NM_018569	PRO0971 hypothetical protein	P + T
			PRO0971
miR-21	AA156948	PRPF4B	PRP4 pre-mRNA	M + T	ATP binding|RNA splicing|nuclear mRNA splicing,
			processing factor 4		via spliceosome|nucleus|protein amino acid
			homolog B (yeast)		phosphorylation|protein serine/threonine kinase
					activity|transferase activity
miR-21	BF337790	PURB	purine-rich element	M + P + T
			binding protein B
miR-21	NM_002869	RAB6A	RAB6A, member RAS	P + T	GTP binding|GTPase activity|Golgi apparatus|protein
			oncogene family		transport|small GTPase mediated signal transduction
miR-21	AL136727	RAB6C	RAB6C, member RAS	P + T	GTP binding|GTPase activity|intracellular|protein
			oncogene family		transport|response to drug|small GTPase mediated
					signal transduction
miR-21	NM_002890	RASA1	RAS p21 protein	P + T	Ras GTPase activator activity|intracellular signaling
			activator (GTPase		cascade
			activating protein) 1
miR-21	NM_005739	RASGRP1	RAS guanyl releasing	P + T	Ras guanyl-nucleotide exchange factor activity|Ras
			protein 1 (calcium and		protein signal transduction|calcium ion
			DAG-regulated)		binding|calcium ion binding|diacylglycerol
					binding|guanyl-nucleotide exchange factor
					activity|membrane fraction|small GTPase mediated
					signal transduction
miR-21	NM_021111	RECK	reversion-inducing-	M + P + T	cell cycle|membrane|membrane
			cysteine-rich protein		fraction|metalloendopeptidase inhibitor
			with kazal motifs		activity|negative regulation of cell cycle|serine-type
					endopeptidase inhibitor activity
miR-21	NM_006915	RP2	retinitis pigmentosa 2	P + T	beta-tubulin folding|membrane|sensory
			(X-linked recessive)		perception|unfolded protein binding|visual perception
miR-21	AA906056	RPS6KA3	ribosomal protein S6	M + T	ATP binding|central nervous system
			kinase, 90 kDa,		development|protein amino acid
			polypeptide 3		phosphorylation|protein serine/threonine kinase
					activity|signal transduction|skeletal
					development|transferase activity
miR-21	NM_002971	SATB1	special AT-rich	M + P + T	double-stranded DNA binding|establishment and/or
			sequence binding		maintenance of chromatin
			protein 1 (binds to		architecture|nucleus|regulation of transcription, DNA-
			nuclear matrix/scaffold-		dependent|transcription factor activity
			associating DNA's)
miR-21	NM_014191	SCN8A	sodium channel, voltage	M + P + T	ATP binding|cation channel activity|cation
			gated, type VIII, alpha		transport|integral to
			polypeptide		membrane|membrane|neurogenesis|sodium ion
					transport|voltage-gated sodium channel
					activity|voltage-gated sodium channel complex
miR-21	AA927480	SKI	v-ski sarcoma viral	M + P + T
			oncogene homolog
			(avian)
miR-21	NM_003983	SLC7A6	solute carrier family 7	P + T	amino acid metabolism|amino acid transport|amino
			(cationic amino acid		acid-polyamine transporter activity|integral to plasma
			transporter, y+ system),		membrane|plasma membrane|protein complex
			member 6		assembly|transport
miR-21	NM_006359	SLC9A6	solute carrier family 9	P + T	antiporter activity|endoplasmic reticulum
			(sodium/hydrogen		membrane|integral to membrane|integral to
			exchanger), isoform 6		membrane|ion
					transport|microsome|mitochondrion|regulation of
					pH|sodium ion transport|sodium:hydrogen antiporter
					activity|solute:hydrogen antiporter activity
miR-21	NM_003076	SMARCD1	SWI/SNF related,	P + T	chromatin remodeling|chromatin remodeling
			matrix associated, actin		complex|regulation of transcription from RNA
			dependent regulator of		polymerase II promoter|transcription coactivator
			chromatin, subfamily d,		activity
			member 1
miR-21	AI669815	SOX2	SRY (sex determining	P + T	establishment and/or maintenance of chromatin
			region Y)-box 2		architecture|nucleus|regulation of transcription, DNA-
					dependent|transcription|transcription factor activity
miR-21	NM_006940	SOX5	SRY (sex determining	P + T	nucleus|regulation of transcription, DNA-
			region Y)-box 5		dependent|transcription|transcription factor
					activity|transcription from RNA polymerase II
					promoter
miR-21	AI808807	SOX7	SRY (sex determining	P + T	DNA binding|nucleus|regulation of transcription,
			region Y)-box 7		DNA-dependent|transcription
miR-21	NM_006717	SPIN	Spindling	P + T	gametogenesis|ribonucleoprotein complex
miR-21	NM_005842	SPRY2	sprouty homolog 2	P + T	cell-cell
			(Drosophila)		signaling|development|membrane|organogenesis|
					regulation of signal transduction
miR-21	NM_006751	SSFA2	sperm specific antigen 2	P + T	plasma membrane
miR-21	NM_006603	STAG2	stromal antigen 2	P + T	cell cycle|chromosome
					segregation|cytokinesis|meiosis|mitosis|
					molecular_function unknown|nucleus
miR-21	BC000627	STAT3	signal transducer and	P + T	JAK-STAT cascade|acute-phase response|calcium ion
			activator of		binding|cell
			transcription 3 (acute-		motility|cytoplasm|hematopoietin/interferon-class
			phase response factor)		(D200-domain) cytokine receptor signal transducer
					activity|intracellular signaling cascade|negative
					regulation of transcription from RNA polymerase II
					promoter|neurogenesis|nucleus|nucleus|regulation of
					transcription, DNA-dependent|signal transducer
					activity|transcription|transcription factor
					activity|transcription factor activity
miR-21	AW138827	TAF5	TAF5 RNA polymerase	P + T	nucleus|regulation of transcription, DNA-
			II, TATA box binding		dependent|transcription factor TFIID
			protein (TBP)-		complex|transcription factor activity
			associated factor,
			100 kDa
miR-21	BF591040	TAGAP	T-cell activation	P + T	GTPase activator activity
			GTPase activating
			protein
miR-21	NM_000358	TGFBI	transforming growth	M + P + T	cell adhesion|cell proliferation|extracellular matrix
			factor, beta-induced,		(sensu Metazoa)|extracellular space|integrin
			68 kDa		binding|negative regulation of cell adhesion|protein
					binding|sensory perception|visual perception
miR-21	NM_000362	TIMP3	tissue inhibitor of	P + T	enzyme inhibitor activity|extracellular matrix (sensu
			metalloproteinase 3		Metazoa)|extracellular matrix (sensu
			(Sorsby fundus		Metazoa)|induction of apoptosis by extracellular
			dystrophy,		signals|metalloendopeptidase inhibitor
			pseudoinflammatory)		activity|sensory perception|visual perception
miR-21	AA149745	TRIM2	tripartite motif-	M + P + T	cytoplasm|myosin binding|protein
			containing 2		ubiquitination|ubiquitin ligase complex|ubiquitin-
					protein ligase activity|zinc ion binding
miR-21	AF346629	TRPM7	transient receptor	P + T	ATP binding|calcium channel activity|calcium ion
			potential cation		transport|cation transport|integral to
			channel, subfamily M,		membrane|membrane|protein amino acid
			member 7		phosphorylation|protein serine/threonine kinase
					activity|transferase activity
miR-21	AI745185	YAP1	Yes-associated protein	P + T
			1, 65 kDa
miR-21	NM_005667	ZFP103	zinc finger protein 103	P + T	central nervous system development|integral to
			homolog (mouse)		membrane|protein ubiquitination|ubiquitin ligase
					complex|ubiquitin-protein ligase activity|zinc ion
					binding
miR-21	N62196	ZNF367	zinc finger protein 367	M + P + T	nucleic acid binding|nucleus|zinc ion binding
M = MiRanda
P = PicTar
T = TargetScan

Example 3

Bio-Pathological Features and microRNA Expression

Materials and Methods

Immunohistochemical Analysis of Breast Cancer Samples.

Staining procedures were performed as described (Querzoli, P., et al., Anal. Quant. Cytol. Histol. 21:151-160 (1999)). Hormonal receptors were evaluated with 6F11 antibody for estrogen receptor α (ER) and PGR-1A6 antibody for progesterone receptor (PR) (Ventana, Tucson, Ariz., U.S.A.). The proliferation index was assessed with MIB1 antibody (DAKO, Copenhagen). ERBB2 was detected with CB11 antibody (Ventana, Tucson, Ariz., U.S.A.) and p53 protein expression was examined with DO7 antibody (Ventana, Tucson, Ariz., U.S.A.). Only tumor cells with distinct nuclear immunostaining for ER, PR, Mib1 and p53 were recorded as positive. Tumor cells were considered positive for ERBB2 when they showed distinct membrane immunoreactivity.

To perform a quantitative analysis of the expression of these various biological markers, the Eureka Menarini computerized image analysis system was used. For each tumor section, at least 20 microscopic fields of invasive carcinoma were measured using a 40× objective. The following cut-off values were employed: 10% of positive nuclear area for ER, PR, c-erbB2 and p53, 13% of nuclei expressing Mib1 was introduced to discriminate cases with high and low proliferative activity.

Results

To evaluate whether a correlation exists between various bio-pathological features associated with breast cancer and the expression of particular miRNAs, we generated and compared miRNA expression profiles for various cancer samples associated with the presence or absence of a particular breast cancer feature. In particular, we analyzed breast cancers with lobular or ductal histotypes, breast cancers with differential expression of either estrogen receptor alpha (ER) or progesterone receptor, and breast cancers with differences in lymph node metastasis, vascular invasion, proliferation index, and expression of ERBB2 and p53.

Expression profiles of lobular or ductal and +/−ERBB2 expression classes did not reveal any microRNAs that were differentially-expressed, while all other comparisons revealed a small number of differentially-expressed microRNAs (P<0.05). The results of this analysis are shown in FIG. 4.

Differentially-expressed miRNA families were identified for various bio-pathological features that are associated with human breast cancer. For example, all miR-30 miRNAs are down-regulated in both ER- and PR-tumors, suggesting that expression of miR-30 miRNAs is regulated by these hormones. In addition, the expression of various let-7 miRNAs was down-regulated in breast cancer samples with either lymph node metastasis or a high proliferation index, suggesting that reduced let-7 expression could be associated with a poor prognosis, a result that is consistent with previous findings. The discovery that the let-7 family of miRNAs regulates the expression of members of the RAS oncogene family provides a potential explanation for the role of let-7 miRNAs in human cancer.

miR-145 and miR-21, two miRNAs whose expression could differentiate cancer or normal tissues, were also differentially-expressed in cancers with a different proliferation index or different tumor stage. In particular, miR-145 is progressively down-regulated from normal breast to cancers with a high proliferation index. Similarly, miR-21 is progressively up-regulated from normal breast to cancers with high tumor stage. These findings suggest that deregulation of these two miRNAs may affect critical molecular events involved in tumor progression.

Another miRNA potentially involved in cancer progression is miR-9-3. miR-9-3 was downregulated in breast cancers with either high vascular invasion or lymph node metastasis, suggesting that its down-regulation was acquired during the course of tumor progression and, in particular, during the acquisition of metastatic potential.

The relevant teachings of all publications cited herein that have not explicitly been incorporated by reference, are incorporated herein by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims