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ZFIN ID: ZDB-PUB-200229-3
DnaJ-PKAc fusion induces liver inflammation in a zebrafish model of Fibrolamellar Carcinoma
de Oliveira, S., Houseright, R.A., Korte, B.G., Huttenlocher, A.
Date: 2020
Source: Disease models & mechanisms   13(4): (Journal)
Registered Authors: de Oliveira, Sofia, Huttenlocher, Anna
Keywords: Early progression, Fibrolamellar Carcinoma, Inflammation, Liver, Non-invasive imaging
MeSH Terms:
  • Aging/pathology
  • Amino Acid Sequence
  • Animals
  • Carcinoma, Hepatocellular/immunology
  • Carcinoma, Hepatocellular/metabolism*
  • Carcinoma, Hepatocellular/pathology*
  • Caspases/metabolism
  • Disease Models, Animal
  • Disease Progression
  • Hepatocytes/metabolism
  • Hepatocytes/pathology
  • Immunity, Innate*
  • Inflammation/pathology*
  • Liver/immunology
  • Liver/pathology*
  • Macrophages/pathology
  • Oncogene Proteins, Fusion/chemistry
  • Oncogene Proteins, Fusion/metabolism*
  • Tumor Necrosis Factor-alpha/metabolism
  • Zebrafish/metabolism*
PubMed: 32102783 Full text @ Dis. Model. Mech.
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ABSTRACT
Fibrolamellar Carcinoma (FLC) is a rare liver cancer that affects adolescents and young adults. Genomic analysis in FLC has revealed a 400 kB deletion in chromosome 19 that leads to a fusion protein, DNAJB1-PRKACA (DnaJ-PKAc) comprised of the first exon of the heat shock protein 40 (DNAJB1) and exons 2-10 of the catalytic subunit of protein kinase A (PRKACA). Here, we report a new zebrafish model of FLC induced by ectopic expression of zebrafish DnaJa-Pkaca (zfDnaJ-Pkaca) in hepatocytes that is amenable to live imaging of early innate immune inflammation. Expression of zfDnaJ-Pkaca in hepatocytes induces hepatomegaly and increased hepatocyte size. In addition, FLC larvae exhibit early innate immune inflammation characterized by early infiltration of neutrophils and macrophages into the liver microenvironment. Increased caspase-a activity was also found in the liver of FLC larvae, and pharmacological inhibition of TNFα and caspase-a decreased liver size and inflammation. Overall, these findings show that innate immune inflammation is an early feature in a zebrafish model of FLC and that that pharmacological inhibition of TNFα or caspase-1 activity might be targets to treat inflammation and progression in FLC.
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