Abstract
Increased angiogenic activity has been demonstrated in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), but the mechanism was unclear. To study the role of HCV core protein, we used tube formation and Matrigel plug assays to assess the proangiogenic activity of an HCC cell line, HuH7, and 2 of its stable clones—HuH7-core-high and HuH7-core-low, with high and low HCV core protein expression, respectively. In both assays, HuH7-core-high and HuH7-core-low cells dose-dependently induced stronger angiogenesis than control cells. HuH7 cells with HCV core protein expression showed increased mRNA and protein expression of vascular endothelial growth factor (VEGF). VEGF inhibition by bevacizumab reduced the proangiogenic activity of HuH7-core-high cells. The promotor region of VEGF contains the binding site of activator protein-1 (AP-1). Compared with controls, HuH7-core-high cells had an increased AP-1 activity and nuclear localization of phospho-c-jun. AP-1 inhibition using either RNA knockdown or AP-1 inhibitors reduced the VEGF mRNA expression and the proangiogenic activity of HuH7-core-high cells. Among 131 tissue samples from HCC patients, HCV-related HCC revealed stronger VEGF expression than did hepatitis B virus-related HCC. In conclusion, increased VEGF expression through AP-1 activation is a crucial mechanism underlying the proangiogenic activity of the HCV core protein in HCC cells.
Highlights
Most patients with hepatocellular carcinoma (HCC) have known etiological factors, such as hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver disease [1,2,3]
The potentiation of the proangiogenic activity of HuH7 cells induced by the HCV core protein was dose dependent, as demonstrated through the more potent angiogenesis induced by HuH7-core-high cells than by HuH7-core-low cells (Figure 1C-1E)
This study revealed that the HCV core protein significantly potentiates the proangiogenic activity of HCC cells both in vitro and in vivo
Summary
Most patients with hepatocellular carcinoma (HCC) have known etiological factors, such as hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver disease [1,2,3]. By evaluation of microvessel density in HCC tumor samples from patients with HBV or HCV infection, HCV-related HCC has been demonstrated to exhibit higher angiogenic activity [4]. The actual molecular mechanism underlying the higher angiogenic activity of HCV-related HCC remains unclear. Previous studies revealed different mechanisms in various experimental models, such as stabilization of hypoxia-inducible factor (HIF)-1α by the subgenomic replicon of HCV [5, 6], increased activity of Jun aminoterminal kinases (JNK), mitogen-activated protein kinase (MAPK), or androgen receptor pathways by the HCV core protein [7, 8], and increased angiopoietin (ANG)-2 expression by the HCV infection [9]. No single study has far demonstrated that HCV can induce angiogenic activity of HCV-related HCC cells through regulating angiogenic pathways in one experimental setting
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