Journal
PEDIATRIC RESEARCH
Volume 80, Issue 1, Pages 110-118Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/pr.2016.36
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Funding
- American Surgical Association Foundation, Beverly, MA
- University of Washington Department of Surgery Research Reinvestment Fund, Seattle, WA
- Herbert S. Coe Foundation, Seattle, WA
- Howard Hughes Medical Institute, Chevy Chase, MD
- National Institutes of Health [DK54111, DK105542]
- Interdisciplinary Training Grant in Cancer [T32 CA080416]
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BACKGROUND: Fibrolamellar hepatocellular carcinoma (FL-HCC) affects children without underlying liver disease. A consistent mutation in FL-HCCs leads to fusion of the genes encoding a heat shock protein (DNAJB1) and the catalytic subunit of protein kinase A (PRKACA). We sought to characterize the resultant chimeric protein and its effects in FL-HCC. METHODS: The expression pattern and subcellular localization of protein kinase A (PKA) subunits in FL-HCCs were compared to paired normal livers by quantitative polymerase chain reaction (qPCR), immunoblotting, and immunofluorescence. PKA activity was measured by radioactive kinase assay, and we determined whether the FL-HCC mutation is present in other primary liver tumors. RESULTS: The fusion transcript and chimeric protein were detected exclusively in FL-HCCs. DNAJB1-PRKACA was expressed 10-fold higher than the wild-type PRKACA transcript, resulting in overexpression of the mutant protein in tumors. Consequently, FL-HCCs possess elevated cAMP-stimulated PKA activity compared to normal livers, despite similar K(m)s between the mutant and wild-type kinases. CONCLUSION: FL-HCCs in children and young adults uniquely overexpress DNAJB1-PRKACA, which results in elevated cAMP-dependent PKA activity. These data suggest that aberrant PKA signaling contributes to liver tumorigenesis.
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