Overwhelming epidemiological evidence links chronic HBV infection with the development of hepatocellular carcinoma (HCC). In some countries including Singapore, an estimated 80% of all HCCs occur in HBV-infected individuals where patients with a chronic infection carry more than 100-fold increased risk for developing HCC compared to uninfected persons. Effective vaccination against HBV has resulted in a decreased incidence of HBV-associated HCC among vaccinated individuals.

The association between chronic HBV infection and HCC remains poorly understood. Two possible HBV-specific mechanisms that contribute to the development of HCC have been proposed. One mechanism is based on the inherent potential of chromosomal integration by the viral genome, while the other mechanism involves the expression of trans-activating factors derived from the HBV genome.

In the first mechanism, integration of the HBV genome has been reported to destabilise the host genome and become clonally propagated in HCCs. In some cases, HBV integrations have been demonstrated to cause activation of tumour-relevant genes (e.g. cyclin A, retinoic receptor γ, mevalonate kinase, and epidermal growth factor receptor (EGFR) -homolog) by promoter/enhancer insertion. In addition, HBV integrations have also been found in or around tumour suppressor loci, suggesting that inactivating mutations may have contributed to the loss of tumour suppressor functions.

In the second mechanism, trans-activating factors encoded by the HBV genome, for example the HBV x-protein (HBx), may lead to alteration of expression of a broad range of host genes and is drawing much attention for its contributory role in HCC. Incorporated into hepatocytes, HBx has been reported to disrupt nucleotide excision repair, inhibit apoptotic cell death, and interfere with the tumour suppressor protein p53 or activation of growth factors. Indeed, in vivo experiments have shown that some strains of transgenic mice over-expressing HBx develop altered hepatocyte morphology, followed by adenomas and HCC. This may also explain why only some people with HBV infection develop cancer.

Unraveling the pleiotropic functions of HBx remains a great challenge, given the likelihood of its multiple targets due to its occurrence in both the cytoplasm and nucleus of cells. However, disentangling the cellular targets and mechanisms of HBx responsible for its oncogenic properties may prove to be fruitful and give rise to possible targets for future treatment modalities. Nonetheless, the first line of defence should be primary prevention against HBV that can be efficiently prevented by vaccination. Nation-wide vaccination programs will serve to reduce the occurrence of HBV-related HCC.

 

Alvin Lee, PhD		Caroline Lee, PhD
Research Fellow		Principal Investigator
Division of Medical Sciences		Division of Medical Sciences
National Cancer Centre, Singapore		National Cancer Centre, Singapore