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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2015; 21(42): 12042-12058
Published online Nov 14, 2015. doi: 10.3748/wjg.v21.i42.12042
Zebrafish as a disease model for studying human hepatocellular carcinoma
Jeng-Wei Lu, Yi-Jung Ho, Yi-Ju Yang, Heng-An Liao, Shih-Ci Ciou, Liang-In Lin, Da-Liang Ou
Jeng-Wei Lu, Yi-Ju Yang, Heng-An Liao, Liang-In Lin, Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Yi-Jung Ho, Institute of Preventive Medicine, National Defense Medical Center, New Taipei 237, Taiwan
Yi-Jung Ho, Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan
Shih-Ci Ciou, Institute of Biotechnology, National Tsing Hua University, Hsinchu 300, Taiwan
Liang-In Lin, Department of Laboratory Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
Da-Liang Ou, Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Author contributions: Lu JW and Ho YJ conceived and designed the research strategy and wrote the paper; Yang YJ, Liao HA and Ciou SC wrote the manuscript; Lin LI and Ou DL critically revised the manuscript for intellectual content.
Supported by Grants from the National Science Council, NSC 102-2314-B-002-142-MY3 and NSC-102-2628-B-002-029-MY3, Taiwan.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest regarding the publication of this paper.
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:
Correspondence to: Da-Liang Ou, PhD, Graduate Institute of Oncology, College of Medicine, National Taiwan University, 5F, No.2, Xuzhou Road, Taipei 100, Taiwan.
Telephone: +886-2-23123456-88662 Fax: +886-2-33936523
Received: April 16, 2015
Peer-review started: April 18, 2015
First decision: May 18, 2015
Revised: May 28, 2015
Accepted: August 31, 2015
Article in press: August 31, 2015
Published online: November 14, 2015

Liver cancer is one of the world’s most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma (HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel small-molecule inhibitors. This review will focus on illustrative examples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts, drug discovery, and drug-induced toxic liver injury.

Keywords: Cancer model, Hepatocellular carcinoma, Liver disease, Zebrafish, Drug screening

Core tip: Hepatocellular carcinoma is one of the major cancers in the world and involves multiple mechanisms of tumor formation. Recently, the zebrafish has gained acceptance as a platform for developmental biology, drug toxicology, and translational medical research, offering innovative methods for studying disease and cancer formation. In this article, we summarize recent advances in the study of HCC based on the zebrafish as a model system through the use of transgenesis tools, genome editing technology, xenografts, drug hepatotoxicity, and novel drug discovery. Finally, we emphasize how each system works and how the technology was used in this cancer model.