Zebrafish as a disease model for studying human hepatocellular carcinoma

Abstract

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; Drug screening; Hepatocellular carcinoma; Liver disease; Zebrafish.

Figure 1

Pathogenesis and risk factors of hepatocellular carcinoma. Hepatocellular carcinoma (HCC) formation results from multiple risk factors, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, alcohol, Aflatoxin, and metabolic diseases. These risk factors induce chronic hepatitis, which activates inflammatory pathways. After decades, this inflammatory stress leads to DNA damage and cell cycle dysregulation in hepatocytes, which eventually leads to the development of HCC from chronic disease states, such as liver fibrosis and cirrhosis. Metabolic diseases progress into fatty liver diseases. NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis.

Figure 2

Schematic representation of programmable engineered nucleases of ZFNs, TALENs and CRISPR/Cas.