Hepatitis C virus infection reduces hepatocellular polarity in a vascular endothelial growth factor-dependent manner

Christopher J. Mee, Michelle J. Farquhar, Helen J. Harris, Ke Hu, Wenda Ramma, Asif Ahmed, Patrick Maurel, Roy Bicknell, Peter Balfe, Jane A. McKeating

Research output: Contribution to journalArticle

Abstract

Background & Aims - 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.
Original languageEnglish
Pages (from-to)1134-1142
Number of pages9
JournalGastroenterology
Volume138
Issue number3
DOIs
Publication statusPublished - Mar 2010

Keywords

  • VEGF
  • tropism
  • HCC
  • angiogenesis

Fingerprint Dive into the research topics of 'Hepatitis C virus infection reduces hepatocellular polarity in a vascular endothelial growth factor-dependent manner'. Together they form a unique fingerprint.

Cite this