m6A抑制的P2RX6激活通过ATP依赖的Ca2+流调节ERK1/2磷酸化和MMP9信号通路促进肾癌细胞迁移和侵袭
背景: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。到目前为止,在RCC中对ATP和P2RX6(ATP的首选受体)的侵袭性机制仍知之甚少。 方法:进行了生物信息学分析,以鉴定RCC不同阶段中差异表达的基因。组织芯片,​​IHC染色和生存分析分别用于评估潜在的临床功能。进行了体外和体内测定以探索P2RX6在RCC进展中的生物学作用。 结果:我们发现ATP可能会增加RCC细胞通过P2RX6的迁移和侵袭。机制剖析表明,ATP-P2RX6可能通过调节Ca 2 + 介导的p-ERK1 / 2 / MMP9信号通路来增加RCC细胞的迁移和侵袭。此外,METTL14涉及RCC中的m 6 A修饰和下调P2RX6蛋白的翻译。此外,人类临床调查还表明,这一新发现的信号在RCC进展和预后中呈正相关。 结论:我们的发现表明,新近鉴定出的ATP-P2RX6-Ca 2 + -p-ERK1 / 2-MMP9信号传导促进RCC细胞的侵袭和转移。用小分子靶向这种新颖的信号传导途径可能有助于我们开发出一种新方法,以更好地抑制RCC进程。**
The m6A-suppressed P2RX6 activation promotes renal cancer cells migration and invasion through ATP-induced Ca2+ influx modulating ERK1/2 phosphorylation and MMP9 signaling pathway
BACKGROUND: 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. METHODS: 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. RESULTS: We found that ATP might increase RCC cells migration and invasion through P2RX6. Mechanism dissection revealed that ATP-P2RX6 might modulate the Ca2+-mediated p-ERK1/2/MMP9 signaling to increase the RCC cells migration and invasion. Furthermore, METTL14 implicated m6A 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. CONCLUSIONS: Our findings revealed that the newly identified ATP-P2RX6-Ca2+-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.
pmid: 31159832 J Exp Clin Cancer Res 影响因子: 5.646 发表日期: 20190603 官网 免费下载
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