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).