MicroRNA silencing of tumor suppressor DLC-1 promotes efficient hepatitis C virus replication in primary human hepatocytes
✍ Scribed by Krishna Banaudha; Michael Kaliszewski; Tamara Korolnek; Liliana Florea; Man Lung Yeung; Kuan-Teh Jeang; Ajit Kumar
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 498 KB
- Volume
- 53
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
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 HCVinfected 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. (HEPATOLOGY 2011;53:53-61) M icroRNAs (miRNAs) originate from highly structured primary transcripts of RNA Pol II genes by way of two-step processing events involving RNase III type nucleases. Primary miRNA transcripts are processed in the nucleus by the RNase III type endonuclease Drosha into precursor and exported to the cytoplasm by exportin 5, to be secondarily cleaved into miRNA duplexes by the cytoplasmic RNase type III Dicer. The resulting miRNA duplexes are incorporated into the RNA-induced silencing complex, where one of the miRNA strands, the passenger, is degraded, while the guide strand complementary to the target messenger RNA (mRNA) serves in target selection and silencing, either by degradation (in case of perfect base complementarity) or inhibition of translation (in case of imperfect sequence complementarity). 1 Thus, the expression of miRNAs in cell type-specific fashion shapes mRNA profiles.
Hepatitis C virus (HCV) is among the most successful of human pathogens. HCV persists in the vast majority of infected individuals as a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) worldwide. The HCV genome is a positive-sense 9.6-kb RNA consisting of a single open reading frame that encodes a large polyprotein complex that is proteolytically cleaved to produce 10