Hepatitis-C-virus core-protein triggers hepatic angiogenesis by a mechanism including multiple-pathways

Objectives: Chronic hepatitis C virus (HCV) infection is associated with the production of serum cytokines including transforming growth factor 2 (TGF)-β2. Although the occurrence of hepatic angiogenesis in liver conditions, the role of HCV protein(s), in this context, is currently unknown.

Methods: Immune fluorescence staining (IF), Concocal Laser Scan Microscopy (CLSM), Western blot analysis, in vitro kinase assay, electrophoretic mobility shift assay (EMSA), Luciferase assay.

Results: We demonstrated the expression of TGF-β2, VEGF, and CD34 in the liver of patients with chronic HCV infection and provided insight into the molecular mechanisms whereby HCV core regulates the development of hepatic angiogenesis. HCV core protein induced TGF-β2 and VEGF expression, and the activation of apoptosis signal-regulating kinase 1 (ASK1), c-jun-N-terminal kinase and p38, and extracellular-regulated kinase (ERK), transcription factors AP-1, ATF-2, CREB, E2F1, HIF-1a and SP1. Inhibition of HCV core protein-induced expression of E2F1 and ASK1 by siRNAs confirmed their role in the modulation of HCV core protein-induced activation of JNK and p38. Whereas, inhibition of HCV core protein-induced TGF-β2 and VEGF production by inhibitors of JNK (Sp600125), p38 (SB-203580), ERK (PD98059) confirmed the role of JNK, p38 and ERK pathways in the regulation of TGF-β2 and VEGF expression in liver cells. Data of luciferase assay showed the contribution of HCV core protein in the regulation of both TGF-β2 and VEGF promotors via multiple pathways.

Conclusion: Our data provide evidence for the contribution of HCV core protein in the development of hepatic angiogenesis, during HCV infection, via a mechanism including multiple pathways.