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Infect Agent Cancer. 2014 Jul 18;9:23. doi: 10.1186/1750-9378-9-23. eCollection 2014.

Loss of nuclear PTEN in HCV-infected human hepatocytes.

Author information

1
Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine, 2300 Eye Street, N.W., Washington, D.C. 20037, USA.
2
McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, MD, USA.
3
Current address: Metabolism Branch, NIH, Bethesda, MD, USA.
4
Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD, USA ; Current address: INSERM U1085-IRSET, Universite de Rennes1, Institut Federatif de Recherche 140, Rennes, France.

Abstract

BACKGROUND:

Hepatitis C virus (HCV) infection is a major risk factor for chronic hepatitis and hepatocellular carcinoma (HCC); however, the mechanism of HCV-mediated hepatocarcinogenesis is not well understood. Insufficiency of PTEN tumor suppressor is associated with more aggressive cancers, including HCC. We asked whether viral non-coding RNA could initiate oncogenesis in HCV infected human hepatocytes. The results presented herein suggest that loss of nuclear PTEN in HCV-infected human hepatocytes results from depletion of Transportin-2, which is a direct target of viral non-coding RNA, vmr11.

METHODS:

The intracellular distribution of PTEN in HCV-infected cells was monitored by immunostaining and Western blots of nuclear and cytoplasmic proteins. Effects of PTEN depletion were examined by comparing expression arrays of uninfected cells with either HCV-infected or vmr11-transfected cells. Target genes suggested by array analyses were validated by Western blot. The influence of nuclear PTEN deficiency on virus production was determined by quantitative analysis of HCV genomic RNA in culture media of infected hepatocytes.

RESULTS:

Import of PTEN to the nucleus relies on the interaction of Transportin-2 and PTEN proteins; we show that depletion of Transportin-2 by HCV infection or by the introduction of vmr11 in uninfected cells results in reduced nuclear PTEN. In turn, nuclear PTEN insufficiency correlates with increased virus production and the induction of γ-H2AX, a marker of DNA double-strand breaks and genomic instability.

CONCLUSION:

An HCV-derived small non-coding RNA inhibits Transportin-2 and PTEN translocation to the nucleus, suggesting a direct viral role in hepatic oncogenesis.

KEYWORDS:

HCV infection; Nuclear PTEN restriction

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