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Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events

Oncogene volume 32, pages 4683–4693 (2013)Cite this article

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Abstract

Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset and development of hepatocellular carcinoma (HCC), although the underlying mechanisms are unclear. The c-Myc oncogene contributes to the genesis of many types of cancers, including HCC, partly via the induction of genetic damage and the inhibition of the cellular response to genotoxic stress. Here, we show a previously undiscovered mechanistic link between HCV infection and enhanced c-Myc expression. c-Myc expression was augmented in non-tumoral liver tissues from HCV-infected individuals with or without HCC and in hepatocyte cell lines harboring an HCV replicon and the infectious HCV strain JFH1. Increased c-Myc expression was confirmed in vivo in a transgenic murine model expressing the entire HCV open reading frame, demonstrating a direct role for HCV protein expression in c-Myc induction. Mechanistically, activation of Akt by the HCV non-structural protein NS5A, and the subsequent stabilization of the transcription factor β-catenin, was demonstrated to be responsible for activation of the c-Myc promoter, and for increased c-Myc transcription. β-Catenin-dependent c-Myc expression in this context led to increased production of reactive oxygen species, mitochondrial perturbation, enhanced DNA damage and aberrant cell-cycle arrest. Together, these data provide a novel insight into the mechanisms involved in HCV-associated HCCs, strongly suggesting that c-Myc has a crucial contributory role in this process.

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Acknowledgements

This work was supported by a research grant from the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS). MH was supported by a postdoctoral fellowship from the ANRS. We thank Aurore Gaudin and Olivier Gouin for technical assistance; Christine Perret and Thomas Decaens for manuscript comments; Czeslaw Wychowski, Bert Vogelstein and Xi He for JFH-1-infected cultures, pDEL1 and DKK1, respectively; Mark Harris for the NS5A antibody; Paulette Bioulac-Sage for patient biopsies; and Ralf Bartenschlager for the HCV genotype 1b subgenomic replicon, established in our laboratory by Abdelhakim Ahmed-Belkacem.

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  1. M R Higgs

    Present address: 3Current address: School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.,

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U955, Institut Mondor de Recherche Biomédicale, Créteil, France

    M R Higgs, H Lerat & J-M Pawlotsky

  2. Department of Virology, National Reference Center for Viral Hepatitis B, C and Delta, Hôpital Henri Mondor, Université Paris-Est, Créteil, France

    J-M Pawlotsky

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Higgs, M., Lerat, H. & Pawlotsky, JM. Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events. Oncogene 32, 4683–4693 (2013). https://doi.org/10.1038/onc.2012.484

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