Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
J Hepatol. 2012 Apr;56(4):803-9. doi: 10.1016/j.jhep.2011.11.018. Epub 2011 Dec 16.
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.
We assessed the effect(s) of HCV and viral glycoprotein expression on hepatoma polarity, migration and invasion.
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.
These data provide new insights into the cancer-promoting effects of HCV infection on HCC migration and offer new approaches for treatment.
丙型肝炎病毒（HCV）可导致进行性肝脏疾病，是肝细胞癌（HCC）发展的主要危险因素。然而，HCV 感染在 HCC 发病机制中的作用仍不清楚。我们研究了 HCV 感染和病毒糖蛋白表达对肝癌生物学的影响，以深入了解与 HCV 相关的 HCC 的发生发展。
我们评估了 HCV 和病毒糖蛋白表达对肝癌极性、迁移和侵袭的影响。
HCV 糖蛋白可破坏紧密连接和黏附连接蛋白的表达，并通过稳定缺氧诱导因子-1α（HIF-1α）增加肝癌的迁移和上皮间质转化标志物 Snail 和 Twist 的表达。HIF-1α 调节许多与肿瘤生长和转移相关的基因，包括血管内皮生长因子（VEGF）和转化生长因子-β（TGF-β）。两种生长因子的中和作用表明 VEGF 和 TGFβ 分别在调节肝癌极性和迁移方面发挥不同的作用。重要的是，我们在病毒感染的肝癌和原代人肝细胞中证实了这些观察结果。抑制 HIF-1α 逆转了感染和糖蛋白表达对肝癌通透性和迁移的影响，并显著降低了 HCV 复制，这表明 HIF-1α 在许多人类癌症和病毒生命周期中失调的细胞过程中具有双重作用。
这些数据为 HCV 感染对 HCC 迁移的致癌作用提供了新的见解，并为治疗提供了新的方法。
