Journal
FASEB JOURNAL
Volume 27, Issue 10, Pages 4027-4040Publisher
WILEY
DOI: 10.1096/fj.13-229187
Keywords
transforming growth factor-; hepatocellular carcinoma; EMT
Categories
Funding
- Institut National du Cancer (INCa)
- Association pour la Recherche contre le Cancer (ARC)
- Agence Nationale pour la Recherche sur le SIDA et les Hepatites Virales (ANRS) [PAIR-CHC 2009-141]
- Ligue Nationale contre le Cancer and the Fondation pour la Recherche Medicale (FRM)
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TGF- signaling induces epithelial to mesenchymal transition (EMT) and plays an important role in hepatocellular carcinoma (HCC) development. Clinical observations indicate that hepatitis C virus (HCV) chronic infection, which is a major cause of HCC, induces TGF- signaling perturbations. Here, we investigate the mechanisms by which HCV nonstructural proteins interfere with TGF- signaling, in human hepatoma cell lines expressing HCV subgenomic replicon. A transcriptomic study showed that TGF- stimulation of these cells resulted in a protumoral gene expression profile and in up-regulation of EMT-related genes compared to control interferon-treated cells not expressing HCV proteins. We found that the viral protease NS3-4A interacted with SMURF2, a negative regulator of TGF- signaling. In cells expressing HCV subgenomic replicon or NS3-4A, TGF- stimulation induced an increased expression of SMAD-dependent genes compared to control cells. This enhanced signaling was suppressed by SMURF2 overexpression and mimicked by SMURF2 silencing. In addition, NS3-4A expression resulted in an increased and prolonged TGF--induced phosphorylation of SMAD2/3 that was abrogated by SMURF2 overexpression. Neither NS3-4A protease activity nor SMURF2 ubiquitin-ligase activity was required to affect TGF- signaling. Therefore, by targeting SMURF2, NS3-4A appears to block the negative regulation of TGF- signaling, increasing the responsiveness of cells to TGF-. Verga-Gerard, A., Porcherot, M., Meyniel-Schicklin, L., Andre, P., Lotteau, V., and Perrin-Cocon, L. Hepatitis C virus/human interactome identifies SMURF2 and the viral protease as critical elements for the control of TGF- signaling.
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