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FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis

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A Correction to this article was published on 13 September 2023

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Abstract

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.

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Fig. 1: FGFR4 correlated with progression and poor prognosis of GBC.
Fig. 2: FGF19 was associated with FGFR4 expression and progression of GBC.
Fig. 3: Both FGF19 and FGFR4 were required in the proliferation and invasion of GBC.
Fig. 4: FGF19 was secreted from GBC cells and activated FGFR4 in an autocrine pathway.
Fig. 5: FGFR4 and FGF19 expression were induced by BA-activated GPBAR1 dependent on EGR1.
Fig. 6: GPBAR1 regulated the transcription and expression of FGF19 and FGFR4 in a Gs-cAMP-EGR1 axis.
Fig. 7: Co-expression of FGF19 and FGFR4 was a more sensitive prognostic factor of GBC.
Fig. 8: The schematic illustration of BA-regulated GBC progression with FGF19–FGFR4 autocrine loop.

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Funding

Our study was supported by the National Natural Science Foundation of China (Grant No. 82072676), the China Postdoctoral Science Foundation (Grant No. 2020M682190), Shandong University Multidisciplinary Research and Innovation Team of Young Scholars (Grant No. 2020QNQT002), Shandong Province Major Research and Design Program (Grant No. 2018GSF118169), Natural Science Foundation of Shandong Province (ZR2019MH008), Jinan City Science and Technology Development Program (Grant No. 201805017, 201805013), the Major Project of Shandong University Clinical Study (Grant No. 2020SDUCRCA018), the Project of Clinical New Techniques of Qilu Hospital affiliated to Shandong Universtiy, Clinical Research Innovation Fund Project (CXPJJH11800001-2018240) and Hengrui Hepatobiliary and Pancreatic Foundation (Grant No.Y-2017-144).

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  1. These authors contributed equally: Tianli Chen, Hongda Liu.

Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China

    Tianli Chen, Zengli Liu, Kangshuai Li, Yue Wang, Jialiang Liu, Zhipeng Li, Wei Zhao, Zongli Zhang & Yunfei Xu

  2. Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Hongda Liu

  3. Department of Pathology, Qilu Hospital of Shandong University, Jinan, China

    Ruixi Qin

  4. Department of General Surgery, Shandong Provincial ENT Hospital, Shandong Provincial ENT Hospital affiliated to Shandong University, Jinan, China

    Zhipeng Li

  5. Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Jinan, China

    Qinglun Gao

  6. Department of Emergency, Qilu Hospital of Shandong University, Jinan, China

    Chang Pan

  7. Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, China

    Fan Yang

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Chen, T., Liu, H., Liu, Z. et al. FGF19 and FGFR4 promotes the progression of gallbladder carcinoma in an autocrine pathway dependent on GPBAR1-cAMP-EGR1 axis. Oncogene 40, 4941–4953 (2021). https://doi.org/10.1038/s41388-021-01850-1

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