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FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib
- Source :
- Journal of Experimental & Clinical Cancer Research : CR
- Publisher :
- Springer Nature
-
Abstract
- Background Sorafenib, a multi-kinase inhibitor, is used as a standard therapy for advanced hepatocellular carcinoma (HCC). However, complete remission has not been achieved and the molecular basis of HCC resistance to sorafenib remains largely unknown. Previous studies have shown that fibroblast growth factor 19 (FGF19) expression correlates with tumor progression and poor prognosis of HCC. Here, we demonstrate the novel role of FGF19 in HCC resistance to sorafenib therapy. Methods FGF19 Knockdown cells were achieved by lentiviral-mediated interference, and FGFR4 knockout cells were achieved by CRISPR-Cas9. Protein levels of FGF19, FGFR4 and c-PARP in various HCC cell lines were measured by Western blotting analysis. Cell viability was determined by MTS assay, apoptosis was determined by DAPI nuclear staining and Western blot of c-PRAP, and ROS generation was determined by DCFH-DA staining and electrochemical biosensor. Results We showed that FGF19, when overexpressed, inhibited the effect of sorafenib on ROS generation and apoptosis in HCC. In contrast, loss of FGF19 or its receptor FGFR4 led to a remarkable increase in sorafenib-induced ROS generation and apoptosis. In addition, knockdown of FGF19 in sorafenib-resistant HCC cells significantly enhanced the sensitivity to sorafenib. Importantly, targeting FGF19/FGFR4 axis by ponatinib, a third-generation inhibitor of chronic myeloid leukemia, overcomes HCC resistance of sorafenib by enhancing ROS-associated apoptosis in sorafenib-treated HCC. Conclusion Our results provide the first evidence that inhibition of FGF19/FGFR4 signaling significantly overcomes sorafenib resistance in HCC. Co-treatment of ponatinib and sorafinib may represent an effective therapeutic approach for eradicating HCC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0478-9) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Oncology
Cancer Research
Hepatocellular carcinoma
FGF19
chemistry.chemical_compound
0302 clinical medicine
Liver Neoplasms
Ponatinib
Myeloid leukemia
Hep G2 Cells
Sorafenib
Up-Regulation
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Signal Transduction
medicine.drug
Niacinamide
medicine.medical_specialty
Carcinoma, Hepatocellular
Cell Survival
03 medical and health sciences
Cell Line, Tumor
Internal medicine
medicine
Humans
Receptor, Fibroblast Growth Factor, Type 4
Viability assay
neoplasms
business.industry
Research
Phenylurea Compounds
Fibroblast growth factor receptor 4
medicine.disease
digestive system diseases
Fibroblast Growth Factors
030104 developmental biology
chemistry
Drug Resistance, Neoplasm
Apoptosis
Tumor progression
Drug resistance
FGFR4
Synergistic effect
Reactive Oxygen Species
business
Subjects
Details
- Language :
- English
- ISSN :
- 17569966
- Volume :
- 36
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental & Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....37c8dbb686e5d2645b53b144b75e3641
- Full Text :
- https://doi.org/10.1186/s13046-016-0478-9