Principal Investigator: Dr. Yi Guo, Ph.D, Associate Consultant – Asst Professor, Dept of Biochemistry and Molecular Biology
A recurring chromosomal deletion on human chromosome 19 was detected in at least 80% of FL-HCC cases, resulting a novel kinase fusion of DNAJB1-PRKACA (Cornella et al., 2015; Honeyman et al., 2014; Xu et al., 2015). While this novel fusion is identified as a potential oncogenic factor, the establishment of the causal and mechanistic relationship between the DNAJB1-PRKACA fusion and FL-HCC is critical for developing targeted cancer therapy.
This study aims to investigate the function of DNAJB1-PRKACA fusion in FL-HCC oncogenesis using both Drosophila and mice models. We established a DNAJB1-PRKACA transgenic Drosophila model and discovered abnormal phenotype affecting both proliferation and differentiation of Drosophila eyes. We also exploited CRISPR/Cas9 genome-engineering technology in murine cultured hepatocytes to recreate the endogenous chromosomal deletion as found in FL-HCC patients. For this Research Grant application, we proposed to 1) characterize the oncogenic and fibrogenic activities of genetic engineered murine hepatocytes in vitro and in vivo; and 2) screen potent therapeutics using the human DNABJ1-PRKACA over-expression model in Drosophila menalogaster. This study will provide essential resources and knowledge for fighting this aggressive hepatocellular carcinoma.