title: Hepatitis C virus infection reduces hepatocellular polarity in a vascular endothelial growth factor-dependent manner.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) infection leads to progressive liver disease, frequently culminating in fibrosis and hepatocellular carcinoma. The mechanisms underlying liver injury in chronic hepatitis C are poorly understood. This study evaluated the role of vascular endothelial growth factor (VEGF) in hepatocyte polarity and HCV infection.
  
  
  METHODS
  We used polarized hepatoma cell lines and the recently described infectious HCV Japanese fulminant hepatitis (JFH)-1 cell culture system to study the role of VEGF in regulating hepatoma permeability and HCV infection.
  
  
  RESULTS
  VEGF negatively regulates hepatocellular tight junction integrity and cell polarity by a novel VEGF receptor 2-dependent pathway. VEGF reduced hepatoma tight junction integrity, induced a re-organization of occludin, and promoted HCV entry. Conversely, inhibition of hepatoma expressed VEGF with the receptor kinase inhibitor sorafenib or with neutralizing anti-VEGF antibodies promoted polarization and inhibited HCV entry, showing an autocrine pathway. HCV infection of primary hepatocytes or hepatoma cell lines promoted VEGF expression and reduced their polarity. Importantly, treatment of HCV-infected cells with VEGF inhibitors restored their ability to polarize, showing a VEGF-dependent pathway.
  
  
  CONCLUSIONS
  Hepatic polarity is critical to normal liver physiology. HCV infection promotes VEGF expression that depolarizes hepatoma cells, promoting viral transmission and lymphocyte migration into the parenchyma that may promote hepatocyte injury.
authors: Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Christopher J
authors: CJ
authors: Mee
authors: Michelle J
authors: MJ
authors: Farquhar
authors: Helen J
authors: HJ
authors: Harris
authors: Ke
authors: K
authors: Hu
authors: Wenda
authors: W
authors: Ramma
authors: Asif
authors: A
authors: Ahmed
authors: Patrick
authors: P
authors: Maurel
authors: Roy
authors: R
authors: Bicknell
authors: Peter
authors: P
authors: Balfe
authors: Jane A
authors: JA
authors: McKeating
mesh_terms: D019898:Autocrine Communication; D001557:Benzenesulfonates / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D016764:Cell Polarity; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008565:Membrane Proteins / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D062793:Occludin; D010539:Permeability; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D000077157:Sorafenib; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D001557:Benzenesulfonates; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2