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-β 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 HCCderived HCV core natural variants on cancer progression through their impact on TGF-β signaling. Principal Findings: We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-β responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-β 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-β responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-β growth inhibitory effects to tumor promoting responses. Conclusion/Significance: Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-β, 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-β responses from cytostatic effects to EMT development.