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Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-β pathway

Oncogene volume 24, pages 6119–6132 (2005)Cite this article

Abstract

Hepatitis C virus (HCV) is a major risk factor for human hepatocellular carcinoma (HCC) but the mechanisms underlying HCV-induced carcinogenesis are still poorly understood. We have hypothesized that viral variants, selected during long-term infection, might contribute to cellular transformation. To address this issue, we have investigated the effect of natural HCV core variants isolated from liver tumors (T), or their non-tumor (NT) counterparts, on the tumor growth factor-β (TGF-β) pathway, a major regulator of cellular proliferation, differentiation and apoptosis. We have found a significant reduction in TGF-β reporter gene activity with the expression of core sequences isolated from liver tumors. In contrast, moderate or no effects were observed with non-tumor mutants or a core reference sequence. The molecular mechanisms have been characterized and involved the inhibition, by tumor-derived cores, of the DNA-binding activity of the Smad3/4 transcription factors complex. This inhibition occurs through a direct interaction between the central domain (amino acids 59–126) of tumor-derived core and the MH1 DNA-binding domain of Smad3, thus preventing its binding to DNA. We have therefore identified a new cell-signaling pathway targeted by HCV core and inhibited by tumor-derived core sequences. These results suggest that during chronic infection, there is selection of viral variants that may promote cell transformation by providing, to clonally expanding cells, resistance to TGF-β antiproliferative effects.

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Acknowledgements

Support for this work was provided by INSERM, the European Community (VIRGIL), the Ligue Nationale Contre le Cancer (LNC), the Association pour la Recherche sur le Cancer (ARC) and the Agence Nationale de Recherches sur le Sida (ANRS). SB is a fellow from the Italian Government and we are grateful to Anna Linda Zignego for having SB working with us. NP was funded by ARC and INSERM. We thank MMC Lai for providing pCV-J4L6S plasmid and C Rice for the FL/Neo HCV replicon cell line. We thank Pr Hannoun, Pitie-Salpetriere Hospital, Paris and Serban Morosan for liver tissue samples.

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  1. Serena Battaglia and Delphine Boucreux: These authors contributed equally to this work

Authors and Affiliations

  1. Inserm U370, Paris V University, Pasteur Institute, 156 rue de Vaugirard, Paris, Cedex 15, 75730, France

    Nicole Pavio, Serena Battaglia, Delphine Boucreux, Rodolphe Sobesky & Christian Brechot

  2. CNRS UMR 8137 and Department of Hematology, Necker Hospital, Paris V University, 149-161 rue de Sevres, Paris, Cedex 15, 75743, France

    Bertrand Arnulf & Olivier Hermine

  3. Department of Internal Medicine, University of Florence, Florence, Italy

    Serena Battaglia

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  1. Nicole Pavio
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Correspondence to Nicole Pavio or Olivier Hermine.

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Pavio, N., Battaglia, S., Boucreux, D. et al. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-β pathway. Oncogene 24, 6119–6132 (2005). https://doi.org/10.1038/sj.onc.1208749

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