Interaction of Hepatitis C Viral Proteins with Cellular Oncoproteins in the Induction of Liver Cancer

Abstract

Hepatitis C virus infection is a major health problem all over the world. A large proportion of patients infected by HCV develop liver cirrhosis or cancer. However, the mechanism(s) remain to be elucidated. Since HCV does not carry any known oncogene, it is thought that interaction between virally encoded proteins and host proteins is responsible for carcinogenesis. Many crucial interactions between HCV-encoded proteins and host proteins have been reported. In this review we focus on the interaction of viral proteins with important regulators of cell cycle-oncoproteins YB-1, p53, and cyclin D1-which play a major role in cell proliferation, apoptosis, DNA repair, and genomic stability. Genetic variants of HCV accumulate in patients and alter these interactions of host cell proteins. It is a battle between the virus and host and the final outcome depends on the winner; if the host succeeds in clearing the virus the patient may not develop serious liver diseases. On the other hand, if the virus dominates by evolving quasispecies which code for altered proteins that interact differently with host proteins, or induce mutations in host protooncogenes, then the patient may develop liver cirrhosis and/or liver cancer.

Study of promoter hypomethylation profiles of RAS oncogenes in hepatocellular carcinoma derived from hepatitis C virus genotype 3a in Pakistani population

“…Different studies show the interaction of HCV proteins including Core, NS2, NS3, NS4a, and NS5a with various oncoproteins (including MYC and RAS) of the host cell, leading to the development of HCC . The role of HCV core protein is already established in the development of liver steatosis and HCC .…”

p53 and RNA viruses: The tug of war

“…Thus, HCV NS5A interacts with and partially sequestrates p53 and hTAFII32 in the cytoplasm and thereby suppresses p53‐mediated transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection (Lan et al, 2002). At least 4 of 10 HCV proteins physically interact with p53 and inhibit its functions, facilitating viral infection and pathogenesis (Guntaka & Padala, 2014).…”

“…Thus, HCV Core modulates several transcriptional and post-translational events and promote cancerous phenotype (Guntaka & Padala, 2014). However, the exact mechanism remains unclear.…”

New Insights to Prevent Liver Fibrosis by Targeting YB-1 and Collagen Genes

“…Structural Organization of YB-1: YB-1 consists of 3 domains -the amino terminal prolinealanine-rich domain (55 amino acids; purple), the DNA and RNA binding Cold Shock Domain (CSD of ~70 amino acids, green) and the C-terminal end charge zipper domain with alternating clusters of positive and negative charges (~200 amino acids, pink and light blue) ( Figure 1). The amino-(purple box) and carboxyl-terminal domains interact with several genes including tumor suppressor genes p53, Rb and the cell cycle protein cyclin D1 (see Figure 1) [40,41]. Down-regulation of YB-1 expression with siRNA or by gene knockout techniques inhibited both cell invasion and migration and also matrix collagenases [39,42].…”

“…YB-1 participates in various signaling circuits in auto-regulatory activities implicated in renal fibrosis [25]. It is also interesting to note that a fragment of YB-1, secreted by immune cells, acts as a ligand for Notch-3 receptor, which is implicated in epithelial-mesenchymal transition (EMT), which appears to play a major role in liver fibrosis leading to cirrhosis and cancer [25,40]. Post-translational modification by phosphorylation of YB-1 at Ser102 has been demonstrated during LPS-induced early stages of inflammation but not during the late phase of inflammation [54].…”