Document Type

Journal Article

Publication Date

2014

Journal

Infectious Agents and Cancer

Volume

Volume 9

Inclusive Pages

Article number 23

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 ?-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.

Comments

Reproduced with permission of BioMed Central Infectious Agents and Cancer.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.

Peer Reviewed

1

Open Access

1

Prediction of small non-coding RNAs from HCV genomic RNA.doc (168 kB)
Prediction of small non-coding RNAs from HCV genomic RNA

Differentially expressed genes in HCV infected vmr11 RNA transfected human hepatocytes.xls (1602 kB)
Differentially expressed genes in HCV infected vmr11 RNA transfected human hepatocytes

Genes enriched in HCV infected and vmr11 RNA transfected human hepatocytes.docx (33 kB)
Genes enriched in HCV infected and vmr11 RNA transfected human hepatocytes

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