Projects per year
Abstract
BACKGROUND AND AIMS: 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, increasehepatoma 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 growth factors show different roles for VEGF and TGF-β in regulating hepatoma polarity and migration, respectively. Importantly, we confirmed these observations in virus infectedhepatoma 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.
Original language | English |
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Journal | Journal of Hepatology |
DOIs | |
Publication status | Published - 15 Dec 2011 |
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- 3 Finished
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The Role of Hepatitis C Virus Glycoprotein-Receptor Polymorphism in Viral Pathogenesis
McKeating, J.
1/01/12 → 30/06/17
Project: Research Councils
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Mechanisms of Hepatitis C Virus Induced Hepatocyte Injury
McKeating, J. & Balfe, P.
1/10/09 → 30/09/12
Project: Research Councils
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A Role for Hepatic Sinusoidal Endothelial Cell Antigen Presentation in the Generation of Immune Tolerance in Hepatitis C
Rowe, I.
1/01/09 → 4/01/12
Project: Research Councils