Abstract
BackgroundPrevious 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.MethodsBioinformatics 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Previous study demonstrated that extracellular also roughlyAdenosine 5′-triphosphate (ATP) could promote cell migration and invasion in multiple human cancers
We used quantitative real-time PCR analysis (qRT-PCR) in 10 paired clinical renal tumor and para-tumors samples and revealed that 8 differentially expressed genes (DEGs) increased in renal tumor samples significantly (Fig. 1b)
P2RX6 mRNA expression correlated with Renal cell carcinoma (RCC) patients overall survival (OS), indicating higher expression of P2RX6 associated with RCC poor prognosis (**P = 0.00175) (Addtional file 8: Figure S1 D)
Summary
Previous study demonstrated that extracellular ATP could promote cell migration and invasion in multiple human cancers. The pro-invasive mechanisms of ATP and P2RX6, a preferred receptor for ATP, are still poorly studied in RCC. Adenosine 5′-triphosphate (ATP) is the main form of intracellular energy for all types of cell and played different roles in multiple cancers development [9, 10] Gong et al Journal of Experimental & Clinical Cancer Research (2019) 38:233 released extracellular, both in physiological and pathological conditions, where it mediates various biological functions via activation of P2 receptors [11,12,13]. P2Y family of G protein-coupled receptors, including P2RY1, 2, 4, 6, 11, 12, 13, 14 [15, 16], which can modulate the adenylate cyclase-cyclic adenosine 3′, 5′-monophosphate pathway or stimulate the phospholipase C (PLC)-Ca2+ signaling pathway [17]
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