MicroRNAs (miRNAs) belong to a class of endogenously expressed non-coding small RNAs that function primarily as gene regulators. Growing evidence suggests that miRNAs play a significant role in tumor development, making them potential biomarkers for cancer diagnosis and prognosis. The miR-17-92 cluster has emerged as an important locus, being highly overexpressed in several cancers in association with cancer development and progression. The miR-17-92 miRNA cluster generates a single polycistronic primary transcript that yields six mature miRNAs: miR-17, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92a. In colon cancer development, the pathophysiologic roles of these transcripts and their targets are largely unknown. In the present study, we performed copy number analyses of the six miRNAs transcribed from the miR-17-92 cluster in colon tumor tissues. We determined that miR-92a was transcribed at higher levels than the other five miRNAs in both adenomas and carcinoma. In addition, miR-92a directly targeted the anti-apoptotic molecule BCL-2-interacting mediator of cell death (BIM) in colon cancer tissues. An anti-miR-92a antagomir induced apoptosis of colon cancer-derived cell lines. These data indicate that miR-92a plays a pivotal role in the development of colorectal carcinoma. (Cancer Sci 2011; 102: 2264-2271 M icroRNAs (miRNAs) belong to a class of endogenously expressed non-coding small RNAs of approximately 22 nucleotides. These small RNAs influence gene regulation by pairing with mRNAs of protein-encoding genes to repress their expression via decreased translational efficiency and ⁄ or mRNA levels.(1) A growing body of evidence suggests that dysregulation of miRNA expression contributes to a wide variety of human diseases, including cancer. Almost 50% of known miRNAs are located within chromosomal regions frequently amplified or deleted in human cancers. (2) Colorectal cancer (CRC) is the second most common cause of cancer deaths in the Western world.(3) A heterogeneous disease, CRC develops from an accumulation of multiple genetic and epigenetic alterations that change global gene expression profiles; it is this genetic progression that contributes to the diverse phenotypes of CRC. A key step in the progression to cancer is genomic instability, which occurs in approximately 5% of adenomas through either microsatellite instability (MSI) or chromosomal instability (CIN). In CRC, CIN induces the development of aneuploid tumors, which exhibit a non-random pattern of chromosomal alterations that frequently include gains at 8q, 13q, and 20q and losses of 8p, 15q, 17p, and 18q.(4) The miR-17-92 cluster, located at 13q, encodes six miRNAs processed from a common precursor transcript. A role for miR-17-92 in the pathogenesis of human cancers has been implicated by the high incidence of amplification in multiple neoplasms, including diffuse large B cell lymphoma (5) and small cell lung cancer.(6,7)Furthermore, miR-92a derived from this cluster is highly expressed in leukemia (8) and hepatocellular carcinoma tissues....

Background:MicroRNA (miRNA, miR)-18a is a member of the miR-17–92 cluster, an important locus that is markedly overexpressed in several cancers and associated with cancer development and progression. However, the mechanism of action of the miR-17–92 cluster and its individual miRNAs are largely unknown.Methods and Results:In this study, we investigated the expression of the miR-17–92 cluster by in situ hybridisation (ISH) assay and copy-number analysis in gastric tissue microarray (TMA) specimens. We determined that miR-18a was present at higher levels than the other five miRNAs in the cluster. In addition, we identified Protein Inhibitor of Activated Signal Transducer and Activator of Transcription 3 (PIAS3) as a direct target of miR-18a in gastric cancer. miR-18a level was positively correlated with levels of Survivin, Bcl-xL, and c-Myc, which are downstream transcriptional targets of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3-induced transcription can be negatively regulated by PIAS3; consistent with this, PIAS3 level was negatively correlated with levels of Survivin, Bcl-xL, and c-Myc.Conclusion:Our findings indicate that miR-18a acts as an oncogene and plays a role in gastric adenocarcinogenesis, at least in part by negatively regulating PIAS3 and thereby modulating expression of STAT3 target genes.

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