Inducible gankyrin overexpression drives hepatocarcinogenesis in a liver-specific zebrafish model

Abstract

Background

Hepatocarcinogenesis is a complex, multistep process that begins with fatty liver, progresses to fibrosis, and ultimately leads to cancer. Numerous etiological factors contribute to this progression, highlighting the importance of developing animal models to facilitate both basic and translational research aimed at discovering new therapeutic strategies. Gankyrin is a key oncoprotein involved in the genetic regulation of liver pathology.

Material and method

To investigate its oncogenic role without the need for cancer cell inoculation or drug treatment, we employed a Tet-On system to drive zebrafish gankyrin overexpression in hepatocytes under the control of the fabp10a promoter. Results: After eight weeks of induction, fabp10a:eGFP-gankyrin transgenic zebrafish spontaneously developed persistent hyperplasia, bile duct hyperplasia, and hepatocellular carcinoma (HCC), demonstrating the oncogenic potential of gankyrin in liver tumorigenesis. In this study, we demonstrate that gankyrin activation drives the progressive development of HCC in zebrafish. Liver-specific overexpression of gankyrin in wild-type zebrafish led to hyperplasia, bile duct hyperplasia, and HCC, establishing a robust zebrafish model for studying liver cancer. Our findings highlight the utility of this model for investigating the molecular mechanisms underlying tumorigenesis.

Conclusion

This study establishes a robust zebrafish model in which liver-specific overexpression of gankyrin induces spontaneous progression from hyperplasia to hepatocellular carcinoma. The model provides a valuable platform for investigating the molecular mechanisms of hepatocarcinogenesis and exploring potential therapeutic strategies.