Mayo Clinic

2016-2018

Kinase Fusion function investigation

Principal Investigator:  Dr. Yi Guo, Associate Consultant /Assistant Professor , Department of Biochemistry and Molecular Biology

Abstract:

Fibrolamellar Hepatocellular Carcinoma (FL-HCC) is a rare type of liver cancer that predominantly occurs in the adolescent and young adult population without any previous liver disease history. Currently, surgical resection remains the only effective therapy for this aggressive cancer. 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.