Abstract
Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development
through direct and indirect mechanisms. HBV-DNA integration into the host genome occurs
at early steps of clonal tumor expansion and induces both genomic instability and
direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression
of the viral regulatory protein HBx and the large envelope protein deregulate the
cellular transcription program and proliferation control and sensitize liver cells
to carcinogenic factors. Epigenetic changes targeting the expression of tumor suppressor
genes occur early in the development of HCC. A major role is played by HBx that is
recruited on cellular chromatin and modulates chromatin dynamics at specific gene
loci. Compared with tumors associated with other risk factors, HBV-related tumors
have a higher rate of chromosomal alterations and p53 inactivation by mutations, overexpress
fetal liver/hepatic progenitor cells genes, and show a specific activation of the
AKT pathway. The wnt/β-catenin pathway is also often activated, but HBV-related tumors
display a low rate of activating β-catenin mutations. All available evidence strongly
supports the notion that chronic HBV infection triggers both common and etiology-specific
oncogenic pathways, thus playing a direct role beyond stimulation of host immune responses
and chronic necroinflammatory liver disease.
Keywords
hepatocellular carcinoma (HCC) - hepatitis B virus (HBV) - HBx protein - epigenetics
- miRNAs
