miR‐92 is a key oncogenic component of the miR‐17–92 cluster in colon cancer

Abstract

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....

miRNA-95 Mediates Radioresistance in Tumors by Targeting the Sphingolipid Phosphatase SGPP1

“…Recently published reports highlight their oncogenic and prognostic potential. For instance, miR-92a promotes esophageal cancer cell migration and invasion in vitro, and high expression of miR-92a correlates with lymph node metastases and poor overall survival in esophageal squamous cell carcinoma and colorectal carcinoma (44)(45)(46). Similarly, miR-18b overexpression promotes proliferation and loss of cell adhesion, and elevated levels of this miR correlates with reduced relapse-free survival in hepatocellular carcinoma (47).…”

microRNA-20a enhances the epithelial-to-mesenchymal transition of colorectal cancer cells by modulating matrix metalloproteinases

“…Aberrant miRNA expression in cancer has been found to participate in several pathological processes, such as EMT and other events contributing to tumorigenesis (8,9). miR-20a is a member of the miR-17-92 cluster, which includes miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19b-l and miR-92-1, and is located on chromosome 13q31 (10). miR-20a has been reported to be associated with EMT in various types of cancers.…”

Regulation of hypometabolism: insights into epigenetic controls

“…Hence, altered miR-22 levels in the intestine during aestivation suggest a role in dampening AKT signaling during hypometabolism. MiR-92 has anti-apoptotic effects in cancer (Tsuchida et al, 2011) and may have a similar role in sea…”