Role of HCV Core gene of genotype 1a and 3a and host gene Cox-2 in HCV-induced pathogenesis

Abstract

BackgroundHepatitis C virus (HCV) Core protein is thought to trigger activation of multiple signaling pathways and play a significant role in the alteration of cellular gene expression responsible for HCV pathogenesis leading to hepatocellular carcinoma (HCC). However, the exact molecular mechanism of HCV genome specific pathogenesis remains unclear. We examined the in vitro effects of HCV Core protein of HCV genotype 3a and 1a on the cellular genes involved in oxidative stress and angiogenesis. We also studied the ability of HCV Core and Cox-2 siRNA either alone or in combination to inhibit viral replication and cell proliferation in HCV serum infected Huh-7 cells.ResultsOver expression of Core gene of HCV 3a genotype showed stronger effect in regulating RNA and protein levels of Cox-2, iNOS, VEGF, p-Akt as compared to HCV-1a Core in hepatocellular carcinoma cell line Huh-7 accompanied by enhanced PGE2 release and cell proliferation. We also observed higher expression levels of above genes in HCV 3a patient's blood and biopsy samples. Interestingly, the Core and Cox-2-specific siRNAs down regulated the Core 3a-enhanced expression of Cox-2, iNOS, VEGF, p-Akt. Furthermore, the combined siRNA treatment also showed a dramatic reduction in viral titer and expression of these genes in HCV serum-infected Huh-7 cells. Taken together, these results demonstrated a differential response by HCV 3a genotype in HCV-induced pathogenesis, which may be due to Core and host factor Cox-2 individually or in combination.ConclusionsCollectively, these studies not only suggest a genotype-specific interaction between key players of HCV pathogenesis but also may represent combined viral and host gene silencing as a potential therapeutic strategy.

Intrahepatic angiopoietin‐2 correlates with chronic hepatitis C progression and is induced in hepatitis C virus replicon systems

“…These data are consistent with earlier studies that reported the important role of Core and NS5A in stimulating the production of several key factors involved in fibrosis (TGF‐β) and angiogenesis (VEGF) through multiple signalling pathways, including PI3K, JNK/p38 and ERK . Also, other studies have described that the structural proteins E1 and E2 may be implicated in pathological regenerative angiogenesis …”

HCV and Oxidative Stress in the Liver

“…Seventh, development of many types of tumors including HCC depends on efficient angiogenesis [145,146]. It was revealed that HCV infection leads to up-regulation of cyclooxygenase 2 (COX-2), increased production of prostaglandin E2 (PGE2), and vascular endothelial growth factor (VEGF) [147,148]—a crucial regulator of angiogenesis and apoptosis prevention [149,150,151]. Interestingly, this was demonstrated using NS5A and core proteins which caused oxidative stress and up-regulation of ROS-sensitive NF-κB transcription factor [50,148].…”

“…It was revealed that HCV infection leads to up-regulation of cyclooxygenase 2 (COX-2), increased production of prostaglandin E2 (PGE2), and vascular endothelial growth factor (VEGF) [147,148]—a crucial regulator of angiogenesis and apoptosis prevention [149,150,151]. Interestingly, this was demonstrated using NS5A and core proteins which caused oxidative stress and up-regulation of ROS-sensitive NF-κB transcription factor [50,148]. It is worth noting that PGE2 also contributes to tumor survival by other mechanisms [152], one of which could be activation of antiapoptotic PI3K/AKT signaling pathway [147].…”

Inhibitory effect of presenilin inhibitor LY411575 on maturation of hepatitis C virus core protein, production of the viral particle and expression of host proteins involved in pathogenicity

“…et al (19). DNA fragments encoding induced iNOS, COX-2 and VEGF were amplified using the primer pairs described by Jahan et al (32).…”