Liu Zengli, Liu Jialiang, Chen Tianli, Wang Yue, Shi Anda, Li Kangshuai, Li Xingyong, Qiu Bo, Zheng Lijie, Zhao Liming, Shu Lizhuang, Lian Shuo, Huang Shaohui, Zhang Zongli, Xu Yunfei
Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
Department of Hepatobiliary Surgery, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250031, Shandong, China.
Oncogene. 2022 May;41(20):2885-2896. doi: 10.1038/s41388-022-02313-x. Epub 2022 Apr 15.
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.
胆管癌（CCA）是一种起源于胆管的高度恶性肿瘤。CCA的预后较差，治疗选择有限。由于获取CCA标本困难，近年来CCA的生物标志物研究进展甚微。SOX9是胆管细胞增殖和分化的重要调节因子。我们对CCA进行了mRNA测序，检索了TCGA数据，并在一个大型CCA队列中检测了SOX9的表达。在WNT3A刺激下，TCF7提高了SOX9的表达和转录。此外，SOX9在CCA组织中显著上调，并被确定为CCA的预后生物标志物。通过mRNA测序和体外/体内验证，我们证明SOX9增强了FGF7和FGFR2的转录和表达。FGF7在CCA患者的胆汁和血清中显著上调，并可能通过自分泌途径激活FGFR2来促进CCA增殖。FGF7和FGFR2的共表达是预后不良的更敏感标志物。SOX9诱导的FGF7和FGFR2过表达是SOX9介导的培米替尼耐药的关键原因。总之，SOX9和FGF7是CCA的预后生物标志物。WNT3A-TCF7-SOX9轴可通过两条独立途径诱导培米替尼耐药：（1）SOX9直接促进FGFR2的转录和表达；（2）SOX9提高FGF7的表达，FGF7可从CCA细胞分泌并通过自分泌途径激活FGFR2磷酸化。
