1. A dual role for hypoxia inducible factor-1α in the hepatitis C virus lifecycle and hepatoma migration
- Author
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Simon C. Afford, Ricky H. Bhogal, Maria L. Simões, Ragai R. Mitry, Garrick K. Wilson, Ian A. Rowe, Stefan G. Hubscher, Peter Balfe, Anil Dhawan, Margaret Ashcroft, Gary M. Reynolds, Claire L. Brimacombe, Zania Stamataki, Christopher J. Mee, Jane A. McKeating, and Nicola F. Fletcher
- Subjects
Vascular Endothelial Growth Factor A ,EMT, epithelial to mesenchymal transition ,Hepacivirus ,medicine.disease_cause ,SR-BI, scavenger receptor class B member 1 ,Virus Replication ,chemistry.chemical_compound ,Hypoxia-Inducible Factor 1-Alpha ,0302 clinical medicine ,Invasion ,Cell Movement ,Transforming Growth Factor beta ,PHH, primary human hepatocytes ,Hypoxia ,VSV-G, vesicular stomatitis virus glycoprotein ,0303 health sciences ,TGFβ, transforming growth factor-beta ,Liver Neoplasms ,Cell Polarity ,HCVcc, hepatitis C virus cell culture ,VEGF, vascular endothelial growth factor ,Hepatitis C ,3. Good health ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Hepatocellular carcinoma ,CMFDA, 5-chloromethylfluorescein diacetate ,Disease Progression ,BC, bile canaliculi ,030211 gastroenterology & hepatology ,Research Article ,Carcinoma, Hepatocellular ,Hepatitis C virus ,TNFα, tumor necrosis factor alpha ,Biology ,Tight Junctions ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Epithelial–mesenchymal transition ,JFH-1, Japanese fulminant hepatitis-1 ,030304 developmental biology ,Glycoproteins ,HIF-1α, hypoxia inducible factor 1 alpha ,Hepatology ,Transforming growth factor beta ,medicine.disease ,Hypoxia-Inducible Factor 1, alpha Subunit ,Virology ,digestive system diseases ,chemistry ,Viral replication ,Cancer research ,biology.protein ,HCC, hepatocellular carcinoma ,MRP-2, multidrug resistant protein-2 - Abstract
Background & 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, 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.
- Published
- 2012