DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma
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 transp...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
Novmber 21, 2017
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2017, Volume: 114, Issue: 50, Pages: 13076-13084 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.1716483114 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1073/pnas.1716483114 Verlag, Volltext: http://www.pnas.org/content/114/50/13076 
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| Author Notes: | Edward R. Kastenhuber, Gadi Lalazar, Shauna L. Houlihan, Darjus F. Tschaharganeh, Timour Baslan, Chi-Chao Chen, David Requena, Sha Tian, Benedikt Bosbach, John E. Wilkinson, Sanford M. Simon, Scott W. Lowe |
| Summary: | 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. |
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| Item Description: | Gesehen am 16.07.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.1716483114 |