Teng YC, Shen ZQ, Kao CH, Tsai TF. Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes. World J Gastroenterol 2016; 22(1): 300-325 [PMID: 26755878 DOI: 10.3748/wjg.v22.i1.300]
Corresponding Author of This Article
Ting-Fen Tsai, PhD, Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, 155 Li-Nong Street, Sec. 2, Beitou, Taipei 112, Taiwan. tftsai@ym.edu.tw
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Topic Highlight
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yuan-Chi Teng, Ting-Fen Tsai, Program in Molecular Medicine, National Yang-Ming University, Taipei 112, Taiwan
Zhao-Qing Shen, Ting-Fen Tsai, Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan
Cheng-Heng Kao, Center of General Education, Chang Gung University, Taoyuan 333, Taiwan
Ting-Fen Tsai, Aging and Health Research Center, National Yang-Ming University, Taipei 112, Taiwan
Ting-Fen Tsai, Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan
Ting-Fen Tsai, Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan
Author contributions: Teng YC, Shen ZQ and Kao CH contributed equally to this work; Teng YC drafted a portion of the manuscript and prepared Table 1; Shen ZQ drafted a portion of the manuscript and prepared Table 2 and Figure 2; Kao CH designed and prepared Figure 1; Tsai TF organized and wrote the final manuscript.
Supported by Research grants from the Ministry of Science and Technology (MOST) in Taiwan, No. NSC99-2628-B-010-001-MY3, MOST 103-2321-B-010-003, MOST 103-2633-H-010-001, MOST 103-2633-B-400-002 and MOST104-3011-B-010-001; and a grant from the Ministry of Education, Aim for the Top University Plan.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ting-Fen Tsai, PhD, Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, 155 Li-Nong Street, Sec. 2, Beitou, Taipei 112, Taiwan. tftsai@ym.edu.tw
Telephone: +886-2-28267293 Fax: +886-2-28280872
Received: May 18, 2015 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 Processing time: 226 Days and 17.8 Hours
Abstract
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.
