Published online Jan 7, 2016. doi: 10.3748/wjg.v22.i1.300
Peer-review started: May 20, 2015
First decision: September 9, 2015
Revised: October 14, 2015
Accepted: November 24, 2015
Article in press: November 24, 2015
Published online: January 7, 2016
The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine.
Core tip: Hepatitis B virus (HBV) viral products, in particular the oncogenic HBV X protein, and mutations of tumor suppressor genes (TSGs) are the driving force of hepatocellular carcinoma (HCC). Inactivation of a recessive TSG requires mutations in both alleles and fits the “two-hit” model. However, haploinsufficiency occurs when one allele is insufficient to confer the full functionality of a TSG; the gene’s effect can be partial or complete depending on tissue type, genetic modifiers/background, and environmental factors. Mouse models play a pivotal role in demonstrating the oncogenic effects of viral products and in establishing the dose-dependency and quantitative differences when analyzing a TSG involved in HCC.