MICROBIOLOGY AND IMMUNOLOGY ON-LINE

Mechanisms of HBV and HCV induced hepatocellular carcinoma

Hepatitis B and Hepatitis C viruses are the most prominent causes of hepatocellular carcinoma (HCC) around the world. Although there are other risk factors, chronic viral infection is very important and is thought to account for at least 70% of cases. The mechanisms by which tumors are formed can be very complex and the exact molecular events that occur during HCC induction in a virus-infected cell are as yet unknown; however, there is evidence to suggest that virus-encoded proteins contribute to transformation. Both hepatitis B x antigen (HBx, a regulatory protein) and hepatitis C core and non-structural proteins appear to interact with a variety of cellular proteins leading to alterations in signal transduction and transcriptional activity. Two of the many proteins with which hepatitis virus proteins interact are Rb and p53 (however, this does not prove that such interactions are the functional basis of oncogenesis).

HBV virus is a member of the hepadnaviridae family and the way it causes a tumor is complex; but integration into host cell DNA occurs at an early stage of cell infection. The expression of the viral HBx protein and the LHBs envelope protein alter control of host cell DNA transcription leading to cell proliferation (thus, these can be termed HBV oncogenes). This may also sensitize the hepatic cells to co-carcinogens (e.g. aflatoxin). Frequently, there is inactivation of p53 tumor suppressor genes, sometimes by mutation or by direct binding of HBx protein to p53 protein (maintaining it in the cytoplasm so that it cannot suppress DNA replication). However, HCC is very much more complex than this and there are many signaling pathway that are modulated by HBV proteins.

HCV is an RNA virus and a member of the flavivirus family. It does not integrate into the host cell genome as it has no DNA provirus form. In HCV-infected cells, a protein called NS5A has been found to bind to p53 (among many other cellular proteins). NS5A is a phosphorylated non-structural protein that displays a multitude of activities related to enhancement of viral pathogenesis.

Initiation of HCC by HBV seems to occur in the early years of life since most patients have experienced a childhood HBV infection. In contrast, HCV-induced HCC often arises after an adult infection. Although HBV integrates into the host cell genome, whereas HCV does not, carcinogenesis induced by both viruses may be similar, not only because it occurs in the liver. Mutations in p53 are common in both HBV- and HCV-induced HCC and even when there is no p53 mutation, normal p53 seems to binds to viral proteins (as does Rb).