Effect of HCV core gene of genotype 3a on HCV induced oxidative stress, steatosis and Apoptosis leading to HCC

Hepatitis C virus (HCV) has become a major threat for global health. HCV genes are thought to activate multiple signaling pathways and play a significant role in the alteration of cellular gene expression responsible for HCV pathogenesis leading to hepatocellular carcinoma (HCC). HCV is genetically highly variable and exist as different genotypes and subtypes, the severity of effect within subtypes and major genotype is diverse. However, the molecular mechanism of HCV genome-specific pathogenesis still remains unclear. So it is crucial to study the cross talk between HCV genes of different genotypes and host factors that lead to HCV induced pathogenesis. The role of the HCV genes of genotype 3a in HCV induced pathogenesis has not been evaluated. In the present study, we observed effect of HCV 3a genotype on expression of genes involved in oxidative stress, steatosis and apoptosis. Transient transfection of HCV Core gene of genotype 3a showed an up-regulation of mRNA expression levels of genes involved in oxidative stress and steatosis and down regulation of genes involved in apoptosis as compare to HCV 1a genotype. When HCV 3a Core genes and host genes expression was blocked by their specific siRNA, dramatic reduction in the expression of cellular genes involved in HCV pathogenesis was observed. Similar results were obtained in HCV-3a serum infected Huh-7 cells. Furthermore, reduction in the viral titer and expression of cellular genes using siRNA against HCV 3a Core and E2 gene and host genes showed the effect on cellular genes involved in HCV pathogenesis. Collectively, these studies not only suggest a genotype-specific crosstalk between key players of HCV pathogenesis but also may represent viral and host genes as therapeutic targets.