title: Hepatitis C viral protein NS5A induces EMT and participates in oncogenic transformation of primary hepatocyte precursors.
abstract: OBJECTIVE
  Apicobasal polarity, which is essential for epithelial structure and function, is targeted by several tumour-related pathogens and is generally perturbed in the course of carcinogenesis. Hepatitis C virus (HCV) infection is associated with a strong risk of hepatocellular carcinoma, typically preceded by dysplastic alterations of cell morphology. We investigated the molecular mechanisms and the functional consequences of HCV-driven perturbations of epithelial polarity.
  
  
  METHODS
  We used biochemical, genetic, and cell biology approaches to assess the impact of hepatitis C viral protein NS5A on the polarity and function of hepatocytes and hepatic progenitors. Transgenic animals and xenograft models served for in vivo validation of the results obtained in cell culture.
  
  
  RESULTS
  We found that expression of HCV-NS5A in primary hepatic precursors and in immortalized hepatocyte cell lines gave rise to profound modifications of cell polarity, leading to epithelial to mesenchymal transition (EMT). NS5A, either alone or in the context of the full complement of viral proteins in the course of infection, acted through activating Twist2, a transcriptional regulator of EMT. The effects of NS5A were additive to those of TGF-β, a cytokine abundant in diseased liver and highly relevant to HCV-related pathology. Moreover, NS5A cooperates with oncogenic Ras, giving rise to transformed, invasive cells that are highly tumorigenic in vivo.
  
  
  CONCLUSIONS
  Our data suggest that in the context of HCV infection, NS5A favors formation of preneoplastic lesions by disrupting cell polarity and additional oncogenic events cooperate with the viral protein to give rise to motile and invasive tumour cells.
authors: Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535, Montpellier, France.
authors: Leila
authors: L
authors: Akkari
authors: Damien
authors: D
authors: Grégoire
authors: Nicolas
authors: N
authors: Floc'h
authors: Marie
authors: M
authors: Moreau
authors: Céline
authors: C
authors: Hernandez
authors: Yannick
authors: Y
authors: Simonin
authors: Arielle R
authors: AR
authors: Rosenberg
authors: Patrice
authors: P
authors: Lassus
authors: Urszula
authors: U
authors: Hibner
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D016764:Cell Polarity / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006526:Hepatitis C / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D012307:Risk Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous; D051879:Twist-Related Protein 1 / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D016283:Proto-Oncogene Proteins p21(ras); D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D051879:Twist-Related Protein 1; D017361:Viral Nonstructural Proteins; C486274:TWIST2 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase