FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis
| Autor: | Hongda Liu, Jialiang Liu, Yunfei Xu, Wei Zhao, Ruixi Qin, Qinglun Gao, Zhipeng Li, Zengli Liu, Tianli Chen, Zongli Zhang, Kangshuai Li, Yue Wang, Chang Pan, Fan Yang |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research EGR1 Biology Fibroblast growth factor Cell Line Receptors G-Protein-Coupled 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Biomarkers Tumor Cyclic AMP Genetics Humans Receptor Fibroblast Growth Factor Type 4 RNA Messenger Autocrine signalling Molecular Biology Cell Proliferation Early Growth Response Protein 1 FGF19 Fibroblast growth factor receptor 4 Prognosis Fibroblast Growth Factors Gene Expression Regulation Neoplastic Autocrine Communication 030104 developmental biology Fibroblast growth factor receptor 030220 oncology & carcinogenesis Disease Progression Cancer research Gallbladder Neoplasms Disease Susceptibility Protein Binding Signal Transduction |
| Zdroj: | Oncogene. 40:4941-4953 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-021-01850-1 |
| Popis: | Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1-/- mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink