Molecular Mechanisms of HBV-Associated Hepatocarcinogenesis

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.

Upregulation of PP2Ac predicts poor prognosis and contributes to aggressiveness in hepatocellular carcinoma

“…HBx is an important oncoprotein involved in the development of HBV-related HCC. 16 We found that HBx-induced HCC cell proliferation, colony formation, and tumor growth were significantly compromised by PP2Ac knockdown, suggesting a mediating role for PP2Ac in the pathogenesis of HBV-related HCC. Clinical data revealed that high PP2Ac expression was significantly associated with histological grade, TNM stage, intrahepatic metastasis, and early recurrence.…”

Presence of Viral DNA in Whole-Genome Sequencing of Brain Tumor Tissues from The Cancer Genome Atlas

“…Viruses that integrate their own DNA into the host's genome can initiate insertional mutagenesis. Hepatitis B virus and certain oncogenic avian viruses provide examples of viruses that can spur carcinogenesis, at least partially, through this mechanism (5,6). Therefore, studies that examine only RNA-Seq data may be unable to completely ascertain whether such viruses could be contributing to carcinogenesis.…”

Prevelance of Common YMDD Motif Mutations in Long Term Treated Chronic HBV Infections in a Turkish Population

“…have also claimed that HBV subgenotypes and mutations in enhancer II, basal core promoter, and precore regions of HBV in relation to risks of liver cirrhosis (LC) and HCC in Southeast China. As claimed by Guerrieri et al (2013) and Yang et al (2013) the mutated YMDD motifs of HBV infection may contributes HCC by inducing both genomic instability and direct insertional mutagenesis of cancer related genes at the early steps of clonal tumor expansion and promote its tumor development by eliciting epigenetic changes.…”