DNAJB1-PRKACA fusion kinase interacts with ß-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma.
Proc Natl Acad Sci U S A
; 114(50): 13076-13084, 2017 12 12.
Article
em En
| MEDLINE
| ID: mdl-29162699
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 ß-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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Fusão Oncogênica
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Carcinoma Hepatocelular
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Beta Catenina
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Proteínas de Choque Térmico HSP40
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Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico
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Fígado
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Neoplasias Hepáticas
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Neoplasias Hepáticas Experimentais
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Regeneração Hepática
Tipo de estudo:
Etiology_studies
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Incidence_studies
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Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article