DNAJB1-PRKACA fusion induces liver inflammation in zebrafish model of Fibrolamellar Hepatocellular Carcinoma
| Autor: | Benjamin G. Korte, Ruth A. Houseright, Sofia de Oliveira, Anna Huttenlocher |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Macrophage polarization Inflammation Biology biology.organism_classification medicine.disease 3. Good health PRKACA 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Fibrolamellar hepatocellular carcinoma 030220 oncology & carcinogenesis Hepatocyte hemic and lymphatic diseases medicine Cancer research Tumor necrosis factor alpha medicine.symptom Liver cancer Zebrafish 030304 developmental biology |
| DOI: | 10.1101/781583 |
| Popis: | Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. Up to now there is only one identified molecular target responsible for driving the disease, the chimeric protein encoded by DNAJB1-PRKACA (J-PKAca). Immune cells have been identified as key players in liver cancer biology, however the effect of J-PKAca on inflammation in the liver microenvironment is not known. Here we report a new zebrafish model of FLC with non-invasive live imaging capabilities that allows the study of the interactions between immune cells and transformed hepatocytes. We found that overexpression of the dnajb1a-prkcaaa fusion gene specifically in hepatocytes induces early malignancy features in FLC transgenic larvae, such as increased liver and hepatocyte size. In addition, this aberrant form of PKA promotes a pro-inflammatory liver microenvironment by increasing the number of neutrophils and macrophages in the liver area and inducing macrophage polarization to a pro-inflammatory phenotype. Increased caspase-a activity was also found in the liver of FLC transgenic larvae. Importantly, pharmacological inhibition of TNFα secretion and caspase-a activity decreased liver size and inflammation. Overall, these findings suggest that inflammation may be an early feature of FLC involved in progression, and that targeting TNFαand caspase-1 may be beneficial in treating FLC. |
| Databáze: | OpenAIRE |
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