title: Hepatitis C virus core variants isolated from liver tumor but not from adjacent non-tumor tissue interact with Smad3 and inhibit the TGF-beta pathway.
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-beta (TGF-beta) pathway, a major regulator of cellular proliferation, differentiation and apoptosis. We have found a significant reduction in TGF-beta 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-beta antiproliferative effects.
authors: Inserm U370, Paris V University, Pasteur Institute, 156 rue de Vaugirard 75730 Paris cedex 15, France. pavio@necker.fr
authors: Nicole
authors: N
authors: Pavio
authors: Serena
authors: S
authors: Battaglia
authors: Delphine
authors: D
authors: Boucreux
authors: Bertrand
authors: B
authors: Arnulf
authors: Rodolphe
authors: R
authors: Sobesky
authors: Olivier
authors: O
authors: Hermine
authors: Christian
authors: C
authors: Brechot
mesh_terms: D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology / Q000821:virology*; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000502:physiology*; D016174:Hepacivirus / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000503:physiopathology / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus