Evaluation of causative relationship between candidate gene/gene cluster and hepatocellular carcinoma

Abstract

Cancer, which involves uncontrolled growth of cells, may occur almost anywhere in the body. There are risk factors correlating to carcinogenesis in different tissues. In this project, I will focus on hepatocarcinogenesis. Expression profiling is a powerful tool to sort cancer-associated genes by studying their aberrant expression patterns implicating their involvement in carcinogenesis. They could also be the consequence of disrupted cellular activities caused by other mutations. Among those aberrantly expressed genes in hepatocellular carcinoma (HCC), two of the highly expressed genes, miR-183/96/182 cluster (miR cluster) and Cell-Cycle-Related Kinase (CCRK), are studied here. These two genetic components have been implicated in tumor formation in other organ tissues, and their expression can promote hepatocyte proliferation in vitro. In this project, in vivo evaluation of their function was performed in transgenic mouse model to verify if they played causative role in HCC. Transgenic mice with a liver-specific promoter driving miRNA cluster expression in liver were generated. However, transgenic mice with high-level CCRK-expression in liver could not be generated possibly due to embryonic lethality caused by early onset of CCRK expression. As a result, spatiotemporal expression using a hormone-inducible expression system to drive cre-mediated recombination of floxed-CCRK transgene was generated for the study. The result showed that ectopically expressing the miR cluster in mouse liver with or without DEN treatment exerted no observable effect in both gross appearance and histology of the liver. The miR cluster alone was not able to cause liver cancer. On the other hand, morphological change and excessive cell proliferation were found in CCRK-expressing liver. These results implied liver-specific expression of CCRK could alter the hepatocyte cell cycle, while morphological change due to over-expression of CCRK required further experimental confirmation.

Date of Award	2013
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology