Hepatitis C virus proteins modulate microRNA expression and chemosensitivity in malignant hepatocytes

Braconi, C. , Valeri, N., Gasparini, P., Huang, N., Taccioli, C., Nuovo, G., Suzuki, T., Croce, C. M. and Patel, T. (2010) Hepatitis C virus proteins modulate microRNA expression and chemosensitivity in malignant hepatocytes. Clinical Cancer Research, 16(3), pp. 957-966. (doi:10.1158/1078-0432.CCR-09-2123) (PMID:20103677) (PMCID:PMC2818698)

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Abstract

Purpose: Hepatocellular cancer (HCC) is highly resistant to chemotherapy and is associated with poor prognosis. Chronic hepatitis C virus (HCV) infection is a major cause of HCC. However, the effect of viral proteins in mediating chemosensitivity in tumor cells is unknown. We postulated that HCV viral proteins could modulate therapeutic responses by altering host cell microRNA (miRNA) expression. Experimental Design: HepG2 malignant hepatocytes were stably transfected with full-length HCV genome (Hep-394) or an empty vector (Hep-SWX). MiRNA profiling was done by using a custom microarray, and the expression of selected miRNAs was validated by real-time PCR. Protein expression was assessed by Western blotting, whereas caspase activation was assessed by a luminometric assay. Results: The IC50 to sorafenib was lower in Hep-394 compared with Hep-SWX control cells. Alterations in miRNA expression occurred with 10 miRNAs downregulated >2-fold and 23 miRNAs upregulated >2-fold in Hep-394 cells compared with controls. Of these, miR-193b was overexpressed by 5-fold in Hep-394 cells. miR-193b was predicted to target Mcl-1, an antiapoptotic protein that can modulate the response to sorafenib. The expression of Mcl-1 was decreased, and basal caspase-3/7 activity and poly ADP ribose polymerase cleavage were increased in Hep-394 cells compared with controls. Moreover, transfection with precursors to miR-193b decreased both Mcl-1 expression and the IC50 to sorafenib. Conclusions: Cellular expression of full-length HCV increases sensitivity to sorafenib by the miRNA-dependent modulation of Mcl-1 and apoptosis. Modulation of miRNA responses may be a useful strategy to enhance response to chemotherapy in HCC.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Braconi, Dr Chiara and Valeri, Dr Nicola
Authors: Braconi, C., Valeri, N., Gasparini, P., Huang, N., Taccioli, C., Nuovo, G., Suzuki, T., Croce, C. M., and Patel, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN:1078-0432
ISSN (Online):1557-3265
Published Online:26 January 2010

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