The epigenetic role of microRNAs in the regulation of host tumor suppressor genes induced by hepatitis C viral infection in primary human hepatocytes.

摘要

Micro-RNAs (miRNAs) are ~22nucleotide non-coding RNAs that constitute cell-type specific inhibitors of target gene expression. Aberrant expression of miRNA has been linked to a variety of cancers, including hepatocellular carcinoma (HCC), although the mechanism remains unclear. Hepatitis C virus (HCV) infection is a major cause chronic liver disease and HCC. Here we report direct role of miRNAs induced in HCV infected primary human hepatocytes, that target tumor suppressor gene, DLC-1(deleted in liver cancer 1, a Rho GTPase-activating protein), which is frequently deleted in HCC, and other solid human tumors. We show that efficient virus replication requires miR-141-mediated suppression of DLC-1. Levels of micro-RNAs miR-141 and miR-200a were accentuated in cells infected with the full length, infectious clones of HCV genotypes 1a, 1b and 2a. Increase in miRNAs correlated with the inhibition of DLC-1 protein in HCV infected cells. Depletion of miR-141 with oligonucleotides complementary to the miRNAs inhibited virus replication; whereas artificially increased levels of miR-141 enhanced HCV replication. HCV-infected hepatocytes showed enhanced cell proliferation that was countered by overexpression of DLC-1. Results suggest a novel mechanism of HCV infection-associated regulation of a tumor suppressor gene with the ability to influence HCV infection-mediated liver cancer.