Molecular Mechanisms and Animal Models of HBV-Related Hepatocellular Carcinoma: With Emphasis on Metastatic Tumor Antigen 1

Abstract

Hepatocellular carcinoma (HCC) is an important cause of cancer death worldwide, and hepatitis B virus (HBV) infection is a major etiology, particularly in the Asia-Pacific region. Lack of sensitive biomarkers for early diagnosis of HCC and lack of effective therapeutics for patients with advanced HCC are the main reasons for high HCC mortality; these clinical needs are linked to the molecular heterogeneity of hepatocarcinogenesis. Animal models are the basis of preclinical and translational research in HBV-related HCC (HBV-HCC). Recent advances in methodology have allowed the development of several animal models to address various aspects of chronic liver disease, including HCC, which HBV causes in humans. Currently, multiple HBV-HCC animal models, including conventional, hydrodynamics-transfection-based, viral vector-mediated transgenic, and xenograft mice models, as well as the hepadnavirus-infected tree shrew and woodchuck models, are available. This review provides an overview of molecular mechanisms and animal models of HBV-HCC. Additionally, the metastatic tumor antigen 1 (MTA1), a cancer-promoting molecule, was introduced as an example to address the importance of a suitable animal model for studying HBV-related hepatocarcinogenesis.

Murine Models of Chronic Viral Infections and Associated Cancers

“…The resulting mice are incapable of eliminating the virus, but can be used to study the HBV-induced immune response and HBV-associated carcinogenesis. HCC was observed to develop in transgenic mice with stable production of HBx, full-size HBsAg, and pre-S mutants [ 55 , 56 ]. Studies with these models demonstrated that viral carcinogenic proteins play an important role and act alone or in combination with human oncogenes to facilitate HCC development by inducing oxidative stress, altering the regulation of host gene expression, and activating the carcinogenic signal transmission pathways [ 56 ].…”

“…HCC was observed to develop in transgenic mice with stable production of HBx, full-size HBsAg, and pre-S mutants [ 55 , 56 ]. Studies with these models demonstrated that viral carcinogenic proteins play an important role and act alone or in combination with human oncogenes to facilitate HCC development by inducing oxidative stress, altering the regulation of host gene expression, and activating the carcinogenic signal transmission pathways [ 56 ]. HBV-transgenic mice were additionally used to study the effects of drugs (including cytokines) designed to prevent HBV progression and to develop strategies to overcome immune tolerance to HBV [ 55 ].…”

“…The limitations are possible to overcome in part by using an exogenous organ- or tissue-specific promoter to control expression of the virus (or viral genes). For example, the constitutive promoter of the albumin gene and the inducible promoter of the metallothionein gene determine transgene expression in the liver [ 56 ].…”