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
Altmetric
Citation Impact
MSK Authors
  1. Scott W Lowe
    177 Lowe
  2. Sha Tian
    4 Tian
  3. Chi-Chao   Chen
    14 Chen
  4. Timour Baslan
    24 Baslan