DNAJB1-PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Academic Article uri icon

Overview

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.

publication date

  • November 21, 2017

Research

keywords

  • Carcinoma, Hepatocellular
  • Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
  • HSP40 Heat-Shock Proteins
  • Liver
  • Liver Neoplasms
  • Liver Neoplasms, Experimental
  • Liver Regeneration
  • Oncogene Proteins, Fusion
  • beta Catenin

Identity

PubMed Central ID

  • PMC5740683

Scopus Document Identifier

  • 85038602502

Digital Object Identifier (DOI)

  • 10.1053/j.gastro.2017.09.008

PubMed ID

  • 29162699

Additional Document Info

volume

  • 114

issue

  • 50