Abstract 2091: MiR-145 functions as a potential tumor suppressor in hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The pathogenesis of HCC has been associated with various genetic and epigenetic alterations, including microRNA dysregulation. In defining the differentially expressed miRNAs in HCC, we previously reported on HCC-specific microRNA deregulations by array-based profiling, which revealed common down-regulations of miR-145. Subsequent verification of miR-145 expression in an independent cohort of 72 HCC cases by qRT-PCR corroborated significant down-regulations in tumors compared to their non-malignant counterparts (49%; paired t-test p=0.026). Transfection of miR-145 into HCC cell lines, HKCI-C2 and HKCI-9, showed a consistent inhibitory effect on both cell viability and proliferation as indicated by MTT and colony formation assays. Flow cytometric analysis on HKCI-C2 further indicated that miR-145 could induce G2/M cell cycle arrest and increase apoptosis. MiR-145 has been shown to target insulin receptor substrate 1 (IRS1) in colorectal cancer. It is known that IRS1 is a substrate of insulin-like growth factor receptor (IGF-1R) in the IGF signaling pathway. In-silico prediction by Targetscan, miRNAda and RNAhybrid suggested that miR-145 might also target IGF-1R and IRS2 along the IGF axis. The effects of miR-145 on these IGF components were hence investigated. Our results from Western blot indicated that IRS1 expression was down-regulated in the presence of miR-145, suggesting that it might also be a target of miR-145 in HCC. Taken together, we found that miR-145 could induce cell cycle arrest and apoptosis in HCC cells, possibly through its effect on IRS1. This study reveals for the first time that miR-145 may act as a tumor suppressor in the liver tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2091.