文章：

TRPA1在胰腺导管腺癌细胞系中促进FGFR2c信号传导及其致癌效应

TRPA1 Contributes to FGFR2c Signaling and to Its Oncogenic Outcomes in Pancreatic Ductal Adenocarcinoma-Derived Cell Lines

原文发布日期：31 January 2024

DOI: 10.3390/cancers16030609

类型: Article

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英文摘要：

Fibroblast growth factor receptor (FGFR) signaling is a key modulator of cellular processes dysregulated in cancer. We recently found that the high expression of the mesenchymal FGFR2c variant in human pancreatic ductal adenocarcinoma (PDAC)-derived cells triggers the PKCε-mediated improvement of EMT and of MCL-1/SRC-dependent cell invasion. Since other membrane proteins can affect the receptor tyrosine kinase signaling, including transient receptor potential channels (TRPs), in this work, we investigated the role of TRPs in the FGFR2c/PKCε oncogenic axis. Our results highlighted that either the FGFR2c/PKCε axis shut-off obtained by shRNA or its sustained activation via ligand stimulation induces TRPA1 downregulation, suggesting a channel/receptor dependence. Indeed, biochemical molecular and immunofluorescence approaches demonstrated that the transient depletion of TRPA1 by siRNA was sufficient to attenuate FGFR2c downstream signaling pathways, as well as the consequent enhancement of EMT. Moreover, the biochemical check of MCL1/SRC signaling and the in vitro assay of cellular motility suggested that TRPA1 also contributes to the FGFR2c-induced enhancement of PDAC cell invasiveness. Finally, the use of a selective channel antagonist indicated that the contribution of TRPA1 to the FGFR2c oncogenic potential is independent of its pore function. Thus, TRPA1 could represent a putative candidate for future target therapies in PDAC.

摘要翻译： 

成纤维细胞生长因子受体（FGFR）信号通路是癌症中细胞过程失调的关键调节因子。我们近期发现，在人胰腺导管腺癌（PDAC）来源细胞中，间充质型FGFR2c变体的高表达会触发PKCε介导的上皮-间质转化（EMT）增强以及MCL-1/SRC依赖性细胞侵袭。鉴于包括瞬时受体电位通道（TRPs）在内的其他膜蛋白可能影响受体酪氨酸激酶信号传导，本研究探讨了TRPs在FGFR2c/PKCε致癌轴中的作用。研究结果表明，无论是通过shRNA关闭FGFR2c/PKCε轴，还是通过配体刺激使其持续激活，均会诱导TRPA1表达下调，提示通道与受体间存在依赖性关系。通过生化分子与免疫荧光方法证实，siRNA瞬时敲低TRPA1足以减弱FGFR2c下游信号通路及其介导的EMT增强效应。此外，对MCL1/SRC信号的生化检测及细胞运动能力的体外实验表明，TRPA1同样参与FGFR2c诱导的PDAC细胞侵袭性增强过程。最后，选择性通道拮抗剂实验显示TRPA1对FGFR2c致癌潜能的贡献不依赖于其孔道功能。因此，TRPA1可能成为未来PDAC靶向治疗的潜在候选靶点。

原文链接：

TRPA1 Contributes to FGFR2c Signaling and to Its Oncogenic Outcomes in Pancreatic Ductal Adenocarcinoma-Derived Cell Lines