title: P2X7R suppression promotes glioma growth through epidermal growth factor receptor signal pathway.
abstract: P2X7 receptor (P2X7R) has been shown to mediate an anticancer effect via apoptosis in different types of cancer. However, whether P2X7R exerts a promoting or suppressive effect on brain glioma is still a controversial issue and its underlying mechanism remains unknown. We showed here that P2X7R 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 P2X7R was markedly downregulated by cells exposure to the P2X7R 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 P2X7R 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 P2X7R 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 P2X7R shRNA notably increased the tumor growth. More importantly, either BBG or P2X7R shRNA could markedly upregulated the expression of EGFR, p-EGFR, HIF-1α and VEGF in glioma cells. In conclusion, P2X7R 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.
authors.affiliation: Department of Radiology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Fang
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Letian
authors.initials: L
authors.lastname: Zhang
authors.forename: Jinhua
authors.initials: J
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.forename: Jianbo
authors.initials: J
authors.lastname: Xiang
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Guangkuo
authors.initials: G
authors.lastname: Guo
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007202:Indicators and Reagents / Q000494:pharmacology; D008297:Male; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D012394:Rosaniline Dyes / Q000494:pharmacology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007202:Indicators and Reagents; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C483803:Egfr protein, rat; D066246:ErbB Receptors; C004692:coomassie Brilliant Blue