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Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition.

Abstract : BACKGROUND: Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. PRINCIPAL FINDINGS: We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. CONCLUSION/SIGNIFICANCE: Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-00457811
Contributor : Mireille Gau <>
Submitted on : Saturday, February 20, 2010 - 1:17:10 PM
Last modification on : Wednesday, October 14, 2020 - 3:58:57 AM
Long-term archiving on: : Friday, June 18, 2010 - 6:15:24 PM

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Serena Battaglia, Nassima Benzoubir, Soizic Nobilet, Pierre Charneau, Didier Samuel, et al.. Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition.. PLoS ONE, Public Library of Science, 2009, 4 (2), pp.e4355. ⟨10.1371/journal.pone.0004355⟩. ⟨pasteur-00457811⟩

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