A dual role for hypoxia inducible factor-1伪 in the hepatitis C virus lifecycle and hepatoma migration

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• 作者：Garrick K. Wilson¹ ; Claire L. Brimacombe¹ ; Ian A. Rowe¹ ; Gary M. Reynolds¹ ; Nicola F. Fletcher¹ ; Zania Stamataki¹ ; Ricky H. Bhogal¹ ; Maria L. Simõ ; es² ; Margaret Ashcroft² ; Simon C. Afford¹ ; Ragai R. Mitry³ ; Anil Dhawan³ ; Christopher J. Mee¹ ; Stefan G. Hü ; bscher¹ ; ⁴ ; Peter Balfe¹ ; ^&dagger ; ; Jane A. McKeating¹ ; ^&dagger ; ; ^{j.a.mckeating@bham.ac.uk}
• 关键词：BC ; bile canaliculi ; CMFDA ; 5-chloromethylfluorescein diacetate ; HCC ; hepatocellular carcinoma ; EMT ; epithelial to mesenchymal transition ; HCVcc ; hepatitis C virus cell culture ; HIF-1伪 ; hypoxia inducible factor 1 alpha ; JFH-1 ; Japanese fulminant hepatiti
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：April, 2012
• 卷：56
• 期：4
• 页码：803-809
• 文件大小：1009 K

摘要

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class="h4">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.

class="h4">Methods

We assessed the effect(s) of HCV and viral glycoprotein expression on hepatoma polarity, migration and invasion.

class="h4">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-1伪 (HIF-1伪). HIF-1伪 regulates many genes involved in tumor growth and metastasis, including vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-尾). Neutralization of both growth factors shows different roles for VEGF and TGF尾 in regulating hepatoma polarity and migration, respectively. Importantly, we confirmed these observations in virus infected hepatoma and primary human hepatocytes. Inhibition of HIF-1伪 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-1伪 in the cellular processes that are deregulated in many human cancers and in the viral life cycle.

class="h4">Conclusions

These data provide new insights into the cancer-promoting effects of HCV infection on HCC migration and offer new approaches for treatment.