title: A dual role for hypoxia inducible factor-1α in the hepatitis C virus lifecycle and hepatoma migration.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) causes progressive liver disease and is a major risk factor for the development of hepatocellular carcinoma (HCC). However, the role of infection in HCC pathogenesis is poorly understood. We investigated the effect(s) of HCV infection and viral glycoprotein expression on hepatoma biology to gain insights into the development of HCV associated HCC.
  
  
  METHODS
  We assessed the effect(s) of HCV and viral glycoprotein expression on hepatoma polarity, migration and invasion.
  
  
  RESULTS
  HCV glycoproteins perturb tight and adherens junction protein expression, and increase hepatoma migration and expression of epithelial to mesenchymal transition markers Snail and Twist via stabilizing hypoxia inducible factor-1α (HIF-1α). HIF-1α regulates many genes involved in tumor growth and metastasis, including vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β). Neutralization of both growth factors shows different roles for VEGF and TGFβ in regulating hepatoma polarity and migration, respectively. Importantly, we confirmed these observations in virus infected hepatoma and primary human hepatocytes. Inhibition of HIF-1α reversed the effect(s) of infection and glycoprotein expression on hepatoma permeability and migration and significantly reduced HCV replication, demonstrating a dual role for HIF-1α in the cellular processes that are deregulated in many human cancers and in the viral life cycle.
  
  
  CONCLUSIONS
  These data provide new insights into the cancer-promoting effects of HCV infection on HCC migration and offer new approaches for treatment.
authors.affiliation: Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Garrick K
authors.initials: GK
authors.lastname: Wilson
authors.forename: Claire L
authors.initials: CL
authors.lastname: Brimacombe
authors.forename: Ian A
authors.initials: IA
authors.lastname: Rowe
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: Nicola F
authors.initials: NF
authors.lastname: Fletcher
authors.forename: Zania
authors.initials: Z
authors.lastname: Stamataki
authors.forename: Ricky H
authors.initials: RH
authors.lastname: Bhogal
authors.forename: Maria L
authors.initials: ML
authors.lastname: Simões
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashcroft
authors.forename: Simon C
authors.initials: SC
authors.lastname: Afford
authors.forename: Ragai R
authors.initials: RR
authors.lastname: Mitry
authors.forename: Anil
authors.initials: A
authors.lastname: Dhawan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mee
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hübscher
authors.forename: Peter
authors.initials: P
authors.lastname: Balfe
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D018450:Disease Progression; D006023:Glycoproteins / Q000502:physiology; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D019108:Tight Junctions / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
chemical_list: D006023:Glycoproteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A