Department of Urology, Shanghai Tenth People's Hospital, School of Medicine in Tongji University, Shanghai, 200072, China.
Department of Urology, Renji Hospital, School of Medicine in Shanghai Jiao Tong University, Shanghai, 200127, China.
J Exp Clin Cancer Res. 2019 Jun 3;38(1):233. doi: 10.1186/s13046-019-1223-y.
Previous study demonstrated that extracellular ATP could promote cell migration and invasion in multiple human cancers. Till now, the pro-invasive mechanisms of ATP and P2RX6, a preferred receptor for ATP, are still poorly studied in RCC.
Bioinformatics analysis was performed to identify the differentially expressed genes during RCC different stages. Tissue microarray, IHC staining and survival analysis was respectively used to evaluate potential clinical function. In vitro and in vivo assays were performed to explore the P2RX6 biological effects in RCC progression.
We found that ATP might increase RCC cells migration and invasion through P2RX6. Mechanism dissection revealed that ATP-P2RX6 might modulate the Ca-mediated p-ERK1/2/MMP9 signaling to increase the RCC cells migration and invasion. Furthermore, METTL14 implicated mA modification in RCC and down-regulated P2RX6 protein translation. In addition, human clinical survey also indicated the positive correlation of this newly identified signaling in RCC progression and prognosis.
Our findings revealed that the newly identified ATP-P2RX6-Ca-p-ERK1/2-MMP9 signaling facilitates RCC cell invasion and metastasis. Targeting this novel signaling pathway with small molecules might help us to develop a new approach to better suppress RCC progression.
先前的研究表明，细胞外 ATP 可以促进多种人类癌症中的细胞迁移和侵袭。迄今为止，ATP 及其首选受体 P2RX6 在肾细胞癌中的促侵袭机制仍研究甚少。
进行生物信息学分析以鉴定肾细胞癌不同阶段的差异表达基因。组织微阵列、免疫组化染色和生存分析分别用于评估潜在的临床功能。体外和体内实验分别用于探讨 P2RX6 在肾细胞癌进展中的生物学作用。
我们发现 ATP 可能通过 P2RX6 增加肾癌细胞的迁移和侵袭。机制剖析表明，ATP-P2RX6 可能通过调节 Ca 介导的 p-ERK1/2/MMP9 信号通路来增加肾癌细胞的迁移和侵袭。此外，METTL14 暗示 mA 修饰与肾细胞癌有关，并下调 P2RX6 蛋白翻译。此外，人体临床调查还表明，在肾细胞癌进展和预后中，这种新鉴定的信号具有正相关性。
我们的研究结果表明，新鉴定的 ATP-P2RX6-Ca-p-ERK1/2-MMP9 信号通路促进了肾癌细胞的侵袭和转移。用小分子靶向该新型信号通路可能有助于我们开发一种新方法来更好地抑制肾细胞癌的进展。
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