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Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx

Oncogene volume 18, pages 4848–4859 (1999)Cite this article

Abstract

Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBV-related HCC. To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV. In the present study, we have compared the effects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis. Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis. Using a panel of engineered mutants we have mapped the growth suppressive effect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic effects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.

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Acknowledgements

We thank R Hellio and F Le Deist for excellent technical assistance for confocal microscopy and FACS analysis, respectively. Thanks go also to Drs B Henglein, A Israel, R d'Anna, H Schaller, S Urban and H Will for helpful discussions, providing material and reagents, and critical reading of the manuscript. H Sirma and C Giannini are recipients of fellowships from DFG, EASL, FRM and FIRC (Fondazione Italiana Ricerca sul Cancro). This work was supported by grants from INSERM, EC, ARC and LNC.

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  1. Hüseyin Sirma and Carlo Giannini: H Sirma and C Giannini contributed equally to this work

Authors and Affiliations

  1. INSERM U370, Carcinogénèse Hépatique et Virologie Moléculaire, Necker Institute, 156 rue de Vaugirard, 75730, Paris, Cedex 15, France

    Hüseyin Sirma, Carlo Giannini, Karine Poussin, Patricia Paterlini, Dina Kremsdorf & Christian Bréchot

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  1. Hüseyin Sirma
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Sirma, H., Giannini, C., Poussin, K. et al. Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. Oncogene 18, 4848–4859 (1999). https://doi.org/10.1038/sj.onc.1202867

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