P2X7R suppression promotes glioma growth through epidermal growth factor receptor signal pathway

Abstract P2X 7 receptor (P2X 7 R) has been shown to mediate an anticancer effect via apoptosis in different types of cancer. However, whether P2X 7 R exerts a promoting or suppressive effect on brain glioma is still a controversial issue and its underlying mechanism remains unknown. We showed here that P2X 7 R suppression exerted a pro-growth effect on glioma through directly promoting cells proliferation and pro-angiogenesis, which was associated with epidermal growth factor receptor (EGFR) signaling. The P2X 7 R was markedly downregulated by cells exposure to the P2X 7 R antagonist, brilliant blue G (BBG), moreover, the cells proliferation was enhanced in a dose-dependent manner and the expression of EGFR or p-EGFR protein was significantly upregulated. By constructing C6 cells with reduced expression of P2X 7 R using shRNA, we also demonstrated strong upregulation in cells proliferation and EGFR/p-EGFR expression. However, this effect of BBG was reversed in the presence of gefitinib or suramin. Magnetic resonance imaging and computed tomography perfusion showed that the BBG or P2X 7 R shRNA promoted the tumor growth by about 40% and 50%, respectively, and significantly increased angiogenesis. Nissl and Ki-67 staining also confirmed that BBG or P2X 7 R shRNA notably increased the tumor growth. More importantly, either BBG or P2X 7 R shRNA could markedly upregulated the expression of EGFR, p-EGFR, HIF-1α and VEGF in glioma cells. In conclusion, P2X 7 R suppression exerts a promoting effect on glioma growth, which is likely to be related to upregulated EGFR, HIF-1α and VEGF expression. These findings provide important clues to the molecular basis of anticancer effect of targeting purinergic receptors.