Molecular basis of hepatocellular carcinoma induced by hepatitis C virus infection

Abstract

Present study outlines a comprehensive view of published information about the underlying mechanisms operational for progression of chronic hepatitis C virus (HCV) infection to development of hepatocellular carcinoma (HCC). These reports are based on the results of animal experiments and human based studies. Although, the exact delineated mechanism is not yet established, there are evidences available to emphasize the involvement of HCV induced chronic inflammation, oxidative stress, insulin resistance, endoplasmic reticulum stress, hepato steatosis and liver fibrosis in the progression of HCV chronic disease to HCC. Persistent infection with replicating HCV not only initiates several liver alterations but also creates an environment for development of liver cancer. Various studies have reported that HCV acts both directly as well as indirectly in promoting this process. Whereas HCV related proteins, like HCV core, E1, E2, NS3 and NS5A, modulate signal pathways dysregulating cell cycle and cell metabolism, the chronic infection produces similar changes in an indirect way. HCV is an RNA virus and does not integrate with host genome and therefore, HCV induced hepatocarcinogenesis pursues a totally different mechanism causing imbalance between suppressors and proto-oncogenes and genomic integrity. However, the exact mechanism of HCC inducement still needs a full understanding of various steps involved in this process.

Keywords: Core; Fibrosis; Hepatitis C virus; Hepatocellular carcinoma; Inflammation; NS5A.

Figure 1

Direct and indirect role of hepatitis C virus in causing hepatocellular carcinoma. Role of hepatitis C virus (HCV) and its structural and non-structural proteins in inducement of hepatocellular carcinoma (HCC) during chronic HCV infection. Viral onset causes various cellular alterations leading to activation of hepatic stellate cells which in turn, produce progressive fibrosis leading to cirrhosis of liver. Simultaneously, HCV also dysregulates cell cycle causing cell proliferation. Both cirrhosis and cell proliferation induce development of HCC. In this figure, the top half portion shows an indirect role of HCV via cellular alterations and causing cirrhosis by inter-related mechanisms and cell dysregulation leading to cell proliferation. The lower half shows a direct role of HCV by interaction of its proteins with various cellular pathways producing different effects as preconditions for inducement of HCC. The link bars show the underlying pathways and the bottom boxes show the end effects. EMT: Epithelial to mesenchymal trans-differentiation; HSCs: Hepatic stellate cells; TGF: Transforming growth factor; PKR: Protein kinase; VEGF: Vascular endothelial growth factor; TNF-α: Tumor necrosis factor-α; PPAR-α: Peroxisome proliferator-activated receptor alpha; ERK: Extracellular signal regulated protein kinase; PKA: Protein kinase A; NF-κB: Nuclear factor-κB.