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Wnt-TCF7-SOX9 axis promotes cholangiocarcinoma proliferation and pemigatinib resistance in a FGF7-FGFR2 autocrine pathway

Oncogene volume 41, pages 2885–2896 (2022)Cite this article

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Abstract

Cholangiocarcinoma (CCA) is a type of highly malignant tumor originating from bile ducts. The prognosis of CCA is poor and the treatment options are limited. The biomarker study of CCA has made little progresses in recent years because of the difficulty to obtain CCA specimens. SOX9 is an important regulator of cholangiocyte proliferation and differentiation. We performed mRNA sequencing of CCA, retrieved TCGA data, and detected SOX9 expression in a large CCA cohort. With WNT3A stimulation, SOX9 expression and transcription was elevated by TCF7. Moreover, SOX9 was substantially up-regulated in CCA tissues and was identified as a prognostic biomarker of CCA. With mRNA sequencing and in vitro/vivo validation, we demonstrated that SOX9 enhanced the transcription and expression of FGF7 and FGFR2. FGF7 was significantly up-regulated in the bile and serum of CCA patients, and may promote CCA proliferation by activating FGFR2 in an autocrine pathway. co-expression of FGF7 and FGFR2 was a more sensitive marker for poor prognosis. SOX9-induced overexpression of FGF7 and FGFR2 was the key reason of SOX9-involved pemigatinib resistance. In conclusion, SOX9 and FGF7 were prognostic biomarkers of CCA. WNT3A-TCF7-SOX9 axis could induce pemigatinib resistance in two independent pathways: (1)SOX9 directly promotes FGFR2 transcription and expression; (2)SOX9 elevates FGF7 expression, which could be secreted from CCA cells and activates FGFR2 phosphorylation in an autocrine pathway.

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Fig. 1: SOX9 expression was promoted by WNT3A-TCF7 signaling, and correlated with poor prognosis in CCA.
Fig. 2: SOX9 was required in TCF7-induced proliferation of CCA.
Fig. 3: SOX9 induced the expression of FGF7 and FGFR2 in CCA.
Fig. 4: FGF7 was required in SOX9-induced proliferation of CCA.
Fig. 5: FGF7 promoted CCA proliferation by activating FGFR2.
Fig. 6: FGF7 was involved in SOX9-induced CCA proliferation in an autocrine pathway.
Fig. 7: SOX9 conferred pemigatinib resistance on CCA cells by elevating FGF7-FGFR2 signaling.
Fig. 8: Schematic depiction of the mechanism of SOX9-induced pemigatinib resistance.

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Funding

Our study was supported by Shandong University Multidisciplinary Research and Innovation Team of Young Scholars (Grant No. 2020QNQT002), Shandong Province Key R&D Program(Major Scientific Innovation Projects,2021CXGC011105), National Natural Science Foundation of China (Grant No. 82072676, 82172791), China Postdoctoral Science Foundation (Grant No. 2020M682190, 2020M682195), Clinical Research Foundation of Shandong University (Grant No. 2020SDUCRCA018), Natural Science Foundation of Shandong Province (ZR2019MH008), Jinan City Science and Technology Development Program (Grant No. 201805017, 201805013), Clinical Research Innovation Fund Project(CXPJJH11800001-2018240), Hengrui Hepatobiliary and Pancreatic Foundation (Grant No.Y-2017-144), Key Research and Development Program of Shandong Province (Grant No. 2019GSF108254), Beijing Medical Award Foundation (YXJL-2020-0785-0967, YXJL-2020-0785-0968).

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  1. These authors contributed equally: Zengli Liu, Jialiang Liu.

Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Zengli Liu, Jialiang Liu, Tianli Chen, Yue Wang, Anda Shi, Kangshuai Li, Bo Qiu, Lijie Zheng, Liming Zhao, Lizhuang Shu, Shuo Lian, Shaohui Huang, Zongli Zhang & Yunfei Xu

  2. Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250031, Shandong, China

    Xingyong Li

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Contributions

LZL and LJL carried out our research. XYF designed all of the experiments and wrote the paper. ZZL, CTL, WY, LXY, ZLJ and QB collected the specimens and perform the follow-up. XYF, LZL and LJL participated in data analysis and interpretation. All of the authors have seen and commented on the manuscript.

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Correspondence to Zongli Zhang or Yunfei Xu.

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Liu, Z., Liu, J., Chen, T. et al. Wnt-TCF7-SOX9 axis promotes cholangiocarcinoma proliferation and pemigatinib resistance in a FGF7-FGFR2 autocrine pathway. Oncogene 41, 2885–2896 (2022). https://doi.org/10.1038/s41388-022-02313-x

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