Hepatitis C virus-related hepatocellular carcinoma: An insight into molecular mechanisms and therapeutic strategies

Abstract

Hepatitis C virus (HCV) infects more than 170 million people worldwide, and thereby becomes a series global health challenge. Chronic infection with HCV is considered one of the major causes of end-stage liver disease including cirrhosis and hepatocellular carcinoma. Although the multiple functions of the HCV proteins and their impacts on the modulation of the intracellular signaling transduction processes, the drive of carcinogenesis during the infection with HCV, is thought to result from the interactions of viral proteins with host cell proteins. Thus, the induction of mutator phenotype, in liver, by the expression of HCV proteins provides a key mechanism for the development of HCV-associated hepatocellular carcinoma (HCC). HCC is considered one of the most common malignancies worldwide with increasing incidence during the past decades. In many countries, the trend of HCC is attributed to several liver diseases including HCV infection. However, the development of HCC is very complicated and results mainly from the imbalance between tumor suppressor genes and oncogenes, as well as from the alteration of cellular factors leading to a genomic instability. Besides the poor prognosis of HCC patients, this type of tumor is quite resistance to the available therapies. Thus, understanding the molecular mechanisms, which are implicated in the development of HCC during the course of HCV infection, may help to design a general therapeutic protocol for the treatment and/or the prevention of this malignancy. This review summarizes the current knowledge of the molecular mechanisms, which are involved in the development of HCV-associated HCC and the possible therapeutic strategies.

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

“…is increasing, leading to development of end-stage liver disease including cirrhosis and HCC [4], it is important to define mechanisms of hepatitis C virus (HCV)-induced liver carcinogenesis with involvement of the Wnt/β-catenin signaling pathway. Already at the beginning of this century more numerous mutations of β-catenin were found to develop in HCV-associated HCC than with HBV-related HCC [5].…”

The possible role of NS3 protease activity of hepatitis C virus on fibrogenesis and miR-122 expression in hepatic stellate cells

“…Different molecular pathways are speculated to be involved in the role that NS3 plays in liver fibrosis. Endogenous expression of NS3 protein inside HSCs is indicated to be fibrotic at comparable levels with core protein (Selimovic et al, 2012). Recent achievements have also suggested that the NS3 protein enhances liver fibrosis through protease activity and via direct binding to TGF-β receptors (Sakata et al, 2013).…”

“…Alteration of gene expression in HCV infected liver cells is supposed to play a profound role in the progression of liver fibrosis, and specific viral proteins are frequently identified to be responsible for this transformation. Modulation of gene expression by HCV NS3 protein is involved in liver disease and counts as a key mediator of disease progression toward persistent disease and clinical outcomes such as liver fibrosis, cirrhosis and HCC (Bataller et al, 2004;Selimovic et al, 2012;Wu et al, 2011;Nguyen et al, 2003). While hepatocytes are the main site of viral repli-cation, some controversial reports have claimed that HCV virus can infect hepatic stellate cells (HSCs) and modulate fibrosis signaling pathways and cell activation/transformation (Selimovic et al, 2012;Wu et al, 2011).…”

Hepatitis C and hepatocellular carcinoma: A review of natural history

“…Various studies have been reported in deregulated pathways of pRb in HCC. [38] TGF-β1 is the most prominent profibrogenic cytokine that can be released from any cell type during inflammation, tissue regeneration, and fibrogenesis. It is an anti-inflammatory cytokine, but TGF-β1 is a well-known tumor promoter too.…”