DNAJB1–PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma Journal Article
| Authors: | Kastenhuber, E. R.; Lalazar, G.; Houlihan, S. L.; Tschaharganeh, D. F.; Baslan, T.; Chen, C. C.; Requena, D.; Tian, S.; Bosbach, B.; Wilkinson, J. E.; Simon, S. M.; Lowe, S. W. |
| Article Title: | DNAJB1–PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma |
| Abstract: | A segmental deletion resulting in DNAJB1–PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here we implement CRISPR-Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of either the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild-type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1–PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which causes tissue injury, inflammation, and fibrosis. Our study validates the DNAJB1–PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC, and establishes a practical model for preclinical studies to identify strategies to treat this disease. |
| Keywords: | protein kinase a; β-catenin; fibrolamellar hepatocellular carcinoma; crispr; mouse cancer models |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 114 |
| Issue: | 50 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2017-12-12 |
| Start Page: | 13076 |
| End Page: | 13084 |
| Language: | English |
| DOI: | 10.1073/pnas.1716483114 |
| PROVIDER: | scopus |
| PUBMED: | 29162699 |
| PMCID: | PMC5740683 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
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