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Hepatology. 2011 Jan;53(1):53-61. doi: 10.1002/hep.24016. Epub 2010 Oct 21.

MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes.

Author information

1
Department of Biochemistry and Molecular Biology, The George Washington University, Washington, DC 20037, USA.

Abstract

MicroRNAs (miRNAs) are approximately 22-nucleotide noncoding RNAs that constitute silencers of target gene expression. Aberrant expression of miRNA has been linked to a variety of cancers, including hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) infection is considered a major cause of chronic liver disease and HCC, although the mechanism of virus infection-associated hepatocarcinogenesis remains unclear. We report a direct role of miRNAs induced in HCV-infected primary human hepatocytes that target the tumor suppressor gene DLC-1 (a Rho GTPase-activating protein), which is frequently deleted in HCC, and other solid human tumors. MicroRNA miR-141 that targets DLC-1 was accentuated in cells infected with HCV genotypes 1a, 1b, and 2a. We present several lines of evidence that efficient HCV replication requires miR-141-mediated suppression of DLC-1. An increase in miR-141 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 intracellular miR-141 enhanced HCV replication. HCV-infected hepatocytes showed enhanced cell proliferation that can be countered by overexpression of DLC-1.

CONCLUSION:

The collective results of this study suggest a novel mechanism of HCV infection-associated miRNA-mediated regulation of a tumor suppressor protein that has the ability to influence cell proliferation and HCV infection-mediated liver cancer.

PMID:
20967756
DOI:
10.1002/hep.24016
[Indexed for MEDLINE]

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