Abstract
Purpose
Purinergic P2X7 receptor (P2X7R) is a gated ion channel for which adenosine triphosphate (ATP) is a ligand. Activated P2X7R is widely expressed in a variety of immune cells and tissues and is involved in a variety of physiological and pathological processes. Studies have confirmed that P2X7R is involved in the regulation of tumor cell growth, stimulating cell proliferation or inducing apoptosis. Recent studies have found that P2X7R is abnormally expressed in lung cancer and is closely related to the carcinogenesis and development of lung cancer. In this paper, we comprehensively describe the structure, function, and genetic polymorphisms of P2X7R. In particular, the role and therapeutic potential of P2X7R in lung cancer are discussed to provide new targets and new strategies for the treatment and prognosis of clinical lung cancer.
Methods
The relevant literature on P2X7R and lung cancer from PubMed databases is reviewed in this article.
Results
P2X7R regulates the function of lung cancer cells by activating multiple intracellular signaling pathways (such as the JNK, Rho, HMGB1 and EMT pathways), thereby affecting cell survival, growth, invasion, and metastasis and patient prognosis. Targeting P2X7R with inhibitors effectively suppresses the growth and metastasis of lung cancer cells.
Conclusion
In summary, P2X7R is expected to become a potential target for the treatment of lung cancer, and more clinical research is needed in the future to explore the effectiveness of P2X7R antagonists as treatments.
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References
Adinolfi E, Callegari MG, Cirillo M et al (2009) Expression of the P2X7 receptor increases the Ca2+ content of the endoplasmic reticulum, activates NFATc1, and protects from apoptosis. J Biol Chem 284:10120–10128. https://doi.org/10.1074/jbc.M805805200
Adinolfi E, Callegari MG, Ferrari D et al (2005) Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth. Mol Biol Cell 16:3260–3272. https://doi.org/10.1091/mbc.e04-11-1025
Adinolfi E, Capece M, Amoroso F et al (2015) Emerging roles of P2X receptors in cancer. Curr Med Chem 22:878–890. https://doi.org/10.2174/0929867321666141012172913
Adinolfi E, De Marchi E, Orioli E et al (2019) Role of the P2X7 receptor in tumor-associated inflammation. Curr Opin Pharmacol 47:59–64. https://doi.org/10.1016/j.coph.2019.02.012
Adinolfi E, Raffaghello L, Giuliani AL et al (2012) Expression of P2X7 receptor increases in vivo tumor growth. Cancer Res 72:2957–2969. https://doi.org/10.1158/0008-5472.CAN-11-1947
Agteresch HJ, Burgers SA, van der Gaast A et al (2003) Randomized clinical trial of adenosine 5'-triphosphate on tumor growth and survival in advanced lung cancer patients. Anticancer Drugs 14:639–644. https://doi.org/10.1097/00001813-200309000-00009
Agteresch HJ, Dagnelie PC, van der Gaast A et al (2000) Randomized clinical trial of adenosine 5'-triphosphate in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 92:321–328. https://doi.org/10.1093/jnci/92.4.321
Amoroso F, Capece M, Rotondo A et al (2015) The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma. Oncogene 34:5240–5251. https://doi.org/10.1038/onc.2014.444
Amoroso F, Salaro E, Falzoni S et al (2016) P2X7 targeting inhibits growth of human mesothelioma. Oncotarget 7:49664–49676. https://doi.org/10.18632/oncotarget.10430
Andrault PM, Schamberger AC, Chazeirat T et al (2019) Cigarette smoke induces overexpression of active human cathepsin S in lungs from current smokers with or without COPD. Am J Physiol Lung Cell Mol Physiol 317:L625–L638. https://doi.org/10.1152/ajplung.00061.2019
Bartlett R, Stokes L, Sluyter R (2014) The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol Rev 66:638–675. https://doi.org/10.1124/pr.113.008003
Baxter M, Eltom S, Dekkak B et al (2014) Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung. Thorax 69:1080–1089. https://doi.org/10.1136/thoraxjnl-2014-205467
Boldrini L, Giordano M, Alì G et al (2014) P2X7 protein expression and polymorphism in non-small cell lung cancer (NSCLC). J Negat Results Biomed 13:16. https://doi.org/10.1186/1477-5751-13-16
Boldrini L, Giordano M, Alì G et al (2015) P2X7 mRNA expression in non-small cell lung cancer: MicroRNA regulation and prognostic value. Oncol Lett 9:449–453. https://doi.org/10.3892/ol.2014.2620
Brenner DR, McLaughlin JR, Hung RJ (2011) Previous lung diseases and lung cancer risk: a systematic review and meta-analysis. PLoS ONE 6:e17479. https://doi.org/10.1371/journal.pone.0017479
Broström JM, Ye ZW, Axmon A et al (2015) Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms. Toxicol Appl Pharmacol 287:222–231. https://doi.org/10.1016/j.taap.2015.06.006
Burnstock G (2013) Introduction and perspective, historical note. Front Cell Neurosci 7:227. https://doi.org/10.3389/fncel.2013.00227
Burnstock G, Knight GE (2018) The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. Purinergic Signal 14:1–18. https://doi.org/10.1007/s11302-017-9593-0
Cabrini G, Falzoni S, Forchap SL et al (2005) A His-155 to Tyr polymorphism confers gain-of-function to the human P2X7 receptor of human leukemic lymphocytes. J Immunol 175:82–89. https://doi.org/10.4049/jimmunol.175.1.82
Camphausen K, Moses MA, Beecken WD et al (2001) Radiation therapy to a primary tumor accelerates metastatic growth in mice. Cancer Res 61:2207–2211
Cao F, Hu LQ, Yao SR et al (2019a) P2X7 receptor: A potential therapeutic target for autoimmune diseases. Autoimmun Rev 18:767–777. https://doi.org/10.1016/j.autrev.2019.06.009
Cao Y, Wang X, Li Y et al (2019b) Extracellular and macropinocytosis internalized ATP work together to induce epithelial-mesenchymal transition and other early metastatic activities in lung cancer. Cancer Cell Int 19:254. https://doi.org/10.1186/s12935-019-0973-0
Cheng ZJ, Miao DL, Su QY et al (2019) THZ1 suppresses human non-small-cell lung cancer cells in vitro through interference with cancer metabolism. Acta Pharmacol Sin 40:814–822. https://doi.org/10.1038/s41401-018-0187-3
Choi JH, Ji YG, Ko JJ et al (2018) Activating P2X7 receptors increases proliferation of human pancreatic cancer cells via ERK1/2 and JNK. Pancreas 47:643–651. https://doi.org/10.1097/MPA.0000000000001055
Cui X, Wan B, Yang Y et al (2019) Carbon nanomaterials stimulate HMGB1 release from macrophages and induce cell migration and invasion. Toxicol Sci 172:398–410. https://doi.org/10.1093/toxsci/kfz190
da Silva Ferreira NC, Alves LA, Soares-Bezerra RJ (2019) Potential therapeutic applications of p2 receptor antagonists: from bench to clinical trials. Curr Drug Targets 20:919–937. https://doi.org/10.2174/1389450120666190213095923
Dardano A, Falzoni S, Caraccio N et al (2009) 1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters. J Clin Endocrinol Metab 94:695–698. https://doi.org/10.1210/jc.2008-1322
de Andrade MP, Bian S, Savio LEB et al (2017) Hyperthermia and associated changes in membrane fluidity potentiate P2X7 activation to promote tumor cell death. Oncotarget 8:67254–67268. https://doi.org/10.18632/oncotarget.18595
De Marchi E, Orioli E, Dal Ben D et al (2016) P2X7 Receptor as a Therapeutic Target. Adv Protein Chem Struct Biol 104:39–79. https://doi.org/10.1016/bs.apcsb.2015.11.004
De Marchi E, Orioli E, Pegoraro A et al (2019) The P2X7 receptor modulates immune cells infiltration, ectonucleotidases expression and extracellular ATP levels in the tumor microenvironment. Oncogene 38:3636–3650. https://doi.org/10.1038/s41388-019-0684-y
Dekali S, Divetain A, Kortulewski T et al (2013) Cell cooperation and role of the P2X7 receptor in pulmonary inflammation induced by nanoparticles. Nanotoxicology 7:1302–1314. https://doi.org/10.3109/17435390.2012.735269
Deli T, Csernoch L (2008) Extracellular ATP and cancer: an overview with special reference to P2 purinergic receptors. Pathol Oncol Res 14:219–231. https://doi.org/10.1007/s12253-008-9071-7
Di Virgilio F, Chiozzi P, Falzoni S et al (1998) Cytolytic P2X purinoceptors. Cell Death Differ 5:191–199. https://doi.org/10.1038/sj.cdd.4400341
Di Virgilio F, Dal Ben D, Sarti AC et al (2017) The P2X7 receptor in infection and inflammation. Immunity 47:15–31. https://doi.org/10.1016/j.immuni.2017.06.020
Di Virgilio F, Ferrari D, Adinolfi E (2009) P2X(7): a growth-promoting receptor-implications for cancer. Purinergic Signal 5:251–256. https://doi.org/10.1007/s11302-009-9145-3
Di Virgilio F, Pelegrín P (2019) Editorial overview: Purinergic P2X receptors in innate immunity and inflammation. Curr Opin Pharmacol 47:141–144. https://doi.org/10.1016/j.coph.2019.05.003
Di Virgilio F, Sarti AC, Falzoni S et al (2018a) Extracellular ATP and P2 purinergic signalling in the tumour microenvironment. Nat Rev Cancer 18:601–618. https://doi.org/10.1038/s41568-018-0037-0
Di Virgilio F, Sarti AC, Grassi F (2018b) Modulation of innate and adaptive immunity by P2X ion channels. Curr Opin Immunol 52:51–59. https://doi.org/10.1016/j.coi.2018.03.026
Duan S, Yu J, Han Z et al (2016) Association between P2RX7 gene and hepatocellular carcinoma susceptibility: a case-control study in a chinese han population. Med Sci Monit 22:1916–1923. https://doi.org/10.12659/msm.895763
Duarte RL, Paschoal ME (2006) Molecular markers in lung cancer: prognostic role and relationship to smoking. J Bras Pneumol 32:56–65. https://doi.org/10.1590/s1806-37132006000100012
Eltom S, Stevenson CS, Rastrick J et al (2011) P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke. PLoS ONE 6:e24097. https://doi.org/10.1371/journal.pone.0024097
Fang WG, Tian XX (2017) Identification of a new pro-invasion factor in tumor microenvironment: progress in function and mechanism of extracellular ATP. Bei**g Da Xue Xue Bao Yi Xue Ban 49:188–195
Feng YH, Li X, Zeng R et al (2006) Endogenously expressed truncated P2X7 receptor lacking the C-terminus is preferentially upregulated in epithelial cancer cells and fails to mediate ligand-induced pore formation and apoptosis. Nucleosides Nucleotides Nucleic Acids 25:1271–1276. https://doi.org/10.1080/15257770600890921
Fernando SL, Saunders BM, Sluyter R et al (2007) A polymorphism in the P2X7 gene increases susceptibility to extrapulmonary tuberculosis. Am J Respir Crit Care Med 175:360–366. https://doi.org/10.1164/rccm.200607-970OC
Ferrari D, Bianchi N, Eltzschig HK et al (2016) MicroRNAs modulate the purinergic signaling network. Trends Mol Med 22:905–918. https://doi.org/10.1016/j.molmed.2016.08.006
Fu Z, Lin Q, Hu B et al (2019) P2X7 PET Radioligand 18F-PTTP for differentiation of lung tumor from inflammation. J Nucl Med 60:930–936. https://doi.org/10.2967/jnumed.118.222547
Furini F, Giuliani AL, Parlati ME et al (2019) P2X7 receptor expression in patients with serositis related to systemic lupus erythematosus. Front Pharmacol 10:435. https://doi.org/10.3389/fphar.2019.00435
Gartland A, Buckley KA, Hipskind RA et al (2003) P2 receptors in bone–modulation of osteoclast formation and activity via P2X7 activation. Crit Rev Eukaryot Gene Expr 13:237–242
Ghalali A, Martin-Renedo J, Högberg J et al (2017) Atorvastatin decreases HBx-induced phospho-Akt in hepatocytes via P2X receptors. Mol Cancer Res 15:714–722. https://doi.org/10.1158/1541-7786.MCR-16-0373
Giannuzzo A, Saccomano M, Napp J et al (2016) Targeting of the P2X7 receptor in pancreatic cancer and stellate cells. Int J Cancer 139:2540–2552. https://doi.org/10.1002/ijc.30380
Giuliani AL, Colognesi D, Ricco T et al (2014) Trophic activity of human P2X7 receptor isoforms A and B in osteosarcoma. PLoS ONE 9:e107224. https://doi.org/10.1371/journal.pone.0107224
Giuliani AL, Sarti AC, Falzoni S et al (2017) The P2X7 Receptor-interleukin-1 liaison. Front Pharmacol 8:123. https://doi.org/10.3389/fphar.2017.00123
Gong QY, Chen Y (2015) Correlation between P2X7 receptor gene polymorphisms and gout. Rheumatol Int 35:1307–1310. https://doi.org/10.1007/s00296-015-3258-5
Greig AV, Linge C, Healy V et al (2003) Expression of purinergic receptors in non-melanoma skin cancers and their functional roles in A431 cells. J Invest Dermatol 121:315–327. https://doi.org/10.1046/j.1523-1747.2003.12379.x
Gu BJ, Sluyter R, Skarratt KK et al (2004) An Arg307 to Gln polymorphism within the ATP-binding site causes loss of function of the human P2X7 receptor. J Biol Chem 279:31287–31295. https://doi.org/10.1074/jbc.M313902200
Gu BJ, Wiley JS (2006) Rapid ATP-induced release of matrix metalloproteinase 9 is mediated by the P2X7 receptor. Blood 107:4946–4953. https://doi.org/10.1182/blood-2005-07-2994
Gu BJ, Zhang W, Worthington RA et al (2001) A Glu-496 to Ala polymorphism leads to loss of function of the human P2X7 receptor. J Biol Chem 276:11135–11142. https://doi.org/10.1074/jbc.M010353200
Haskell CM, Mendoza E, Pisters KM et al (1998) Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer. Invest New Drugs 16:81–85. https://doi.org/10.1023/A:1006018610986
Haskell CM, Wong M, Williams A et al (1996) Phase I trial of extracellular adenosine 5'-triphosphate in patients with advanced cancer. Med Pediatr Oncol 27:165–173. https://doi.org/10.1002/(SICI)1096-911X(199609)27:3<165:AID-MPO6>3.0.CO;2-C
Hill LM, Gavala ML, Lenertz LY et al (2010) Extracellular ATP may contribute to tissue repair by rapidly stimulating purinergic receptor X7-dependent vascular endothelial growth factor release from primary human monocytes. J Immunol 185:3028–3034. https://doi.org/10.4049/jimmunol.1001298
Hirsch FR, Scagliotti GV, Mulshine JL et al (2017) Lung cancer: current therapies and new targeted treatments. Lancet 389:299–311. https://doi.org/10.1016/S0140-6736(16)30958-8
Huang S, Chen Y, Wu W et al (2013) miR-150 promotes human breast cancer growth and malignant behavior by targeting the pro-apoptotic purinergic P2X7 receptor. PLoS ONE 8:e80707. https://doi.org/10.1371/journal.pone.0080707
Huang C, Jacobson K, Schaller MD (2004) MAP kinases and cell migration. J Cell Sci 117:4619–4628. https://doi.org/10.1242/jcs.01481
Humphreys BD, Rice J, Kertesy SB et al (2000) Stress-activated protein kinase/JNK activation and apoptotic induction by the macrophage P2X7 nucleotide receptor. J Biol Chem 275:26792–26798. https://doi.org/10.1074/jbc.M002770200
Husted LB, Harsløf T, Stenkjær L et al (2013) Functional polymorphisms in the P2X7 receptor gene are associated with osteoporosis. Osteoporos Int 24:949–959. https://doi.org/10.1007/s00198-012-2035-5
Jelassi B, Anchelin M, Chamouton J et al (2013) Anthraquinone emodin inhibits human cancer cell invasiveness by antagonizing P2X7 receptors. Carcinogenesis 34:1487–1496. https://doi.org/10.1093/carcin/bgt099
Jelassi B, Chantôme A, Alcaraz-Pérez F et al (2011) P2X(7) receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness. Oncogene 30:2108–2122. https://doi.org/10.1038/onc.2010.593
Jørgensen NR, Henriksen Z, Sørensen OH et al (2002) Intercellular calcium signaling occurs between human osteoblasts and osteoclasts and requires activation of osteoclast P2X7 receptors. J Biol Chem 277:7574–7580. https://doi.org/10.1074/jbc.M104608200
Kessler S, Clauss WG, Günther A et al (2011) Expression and functional characterization of P2X receptors in mouse alveolar macrophages. Pflugers Arch 462:419–430. https://doi.org/10.1007/s00424-011-0980-z
Kos J, Sekirnik A, Kopitar G et al (2001) Cathepsin S in tumours, regional lymph nodes and sera of patients with lung cancer: relation to prognosis. Br J Cancer 85:1193–1200. https://doi.org/10.1054/bjoc.2001.2057
Lin TY, Huang WY, Lin JC et al (2014) Increased lung cancer risk among patients with pneumococcal pneumonia: a nationwide population-based cohort study. Lung 192:159–165. https://doi.org/10.1007/s00408-013-9523-z
Lorenzo-González M, Torres-Durán M, Barbosa-Lorenzo R et al (2019) Radon exposure: a major cause of lung cancer. Expert Rev Respir Med 13:839–850. https://doi.org/10.1080/17476348.2019.1645599
Lucattelli M, Cicko S, Müller T et al (2011) P2X7 receptor signaling in the pathogenesis of smoke-induced lung inflammation and emphysema. Am J Respir Cell Mol Biol 44:423–429. https://doi.org/10.1165/rcmb.2010-0038OC
Ma J, Li W, Chai Q et al (2019) Correlation of P2RX7 gene rs1718125 polymorphism with postoperative fentanyl analgesia in patients with lung cancer. Medicine (Baltimore) 98:e14445. https://doi.org/10.1097/MD.0000000000014445
Magkrioti C, Oikonomou N, Kaffe E et al (2018) The autotaxin-lysophosphatidic acid axis promotes lung carcinogenesis. Cancer Res 78:3634–3644. https://doi.org/10.1158/0008-5472.CAN-17-3797
Mehta N, Kaur M, Singh M et al (2014) Purinergic receptor P2X7: a novel target for anti-inflammatory therapy. Bioorg Med Chem 22:54–88. https://doi.org/10.1016/j.bmc.2013.10.054
Mikoczy Z, Welinder H, Tinnerberg H et al (2004) Cancer incidence and mortality of isocyanate exposed workers from the Swedish polyurethane foam industry: updated findings 1959–98. Occup Environ Med 61:432–437. https://doi.org/10.1136/oem.2003.009712
Miraglia E, Högberg J, Stenius U (2012) Statins exhibit anticancer effects through modifications of the pAkt signaling pathway. Int J Oncol 40:867–875. https://doi.org/10.3892/ijo.2011.1223
Mistafa O, Ghalali A, Kadekar S et al (2010) Purinergic receptor-mediated rapid depletion of nuclear phosphorylated Akt depends on pleckstrin homology domain leucine-rich repeat phosphatase, calcineurin, protein phosphatase 2A, and PTEN phosphatases. J Biol Chem 285:27900–27910. https://doi.org/10.1074/jbc.M110.117093
Mistafa O, Högberg J, Stenius U (2008) Statins and ATP regulate nuclear pAkt via the P2X7 purinergic receptor in epithelial cells. Biochem Biophys Res Commun 365:131–136. https://doi.org/10.1016/j.bbrc.2007.10.148
Monção-Ribeiro LC, Faffe DS, Santana PT et al (2014) P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica. PLoS ONE 9:e110185. https://doi.org/10.1371/journal.pone.0110185
Morelli A, Chiozzi P, Chiesa A et al (2003) Extracellular ATP causes ROCK I-dependent bleb formation in P2X7-transfected HEK293 cells. Mol Biol Cell 14:2655–2664. https://doi.org/10.1091/mbc.02-04-0061
Myrtek D, Müller T, Geyer V et al (2008) Activation of human alveolar macrophages via P2 receptors: coupling to intracellular Ca2+ increases and cytokine secretion. J Immunol 181:2181–2188. https://doi.org/10.4049/jimmunol.181.3.2181
Narumiya S, Tanji M, Ishizaki T (2009) Rho signaling, ROCK and mDia1, in transformation, metastasis and invasion. Cancer Metastasis Rev 28:65–76. https://doi.org/10.1007/s10555-008-9170-7
Newbolt A, Stoop R, Virginio C et al (1998) Membrane topology of an ATP-gated ion channel (P2X receptor). J Biol Chem 273:15177–15182. https://doi.org/10.1074/jbc.273.24.15177
Nishimaki N, Tsukimoto M, Kitami A et al (2012) Autocrine regulation of γ-irradiation-induced DNA damage response via extracellularnucleotides-mediated activation of P2Y6 and P2Y12 receptors. DNA Repair (Amst) 11:657–665. https://doi.org/10.1016/j.dnarep.2012.05.005
Ohshima Y, Tsukimoto M, Takenouchi T et al (2010) gamma-Irradiation induces P2X(7) receptor-dependent ATP release from B16 melanoma cells. Biochim Biophys Acta 1800:40–46. https://doi.org/10.1016/j.bbagen.2009.10.008
Oliveira MB, Mello FC, Paschoal ME (2016) The relationship between lung cancer histology and the clinicopathological characteristics of bone metastases. Lung Cancer 96:19–24. https://doi.org/10.1016/j.lungcan.2016.03.014
Orioli E, De Marchi E, Giuliani AL et al (2017) P2X7 Receptor orchestrates multiple signalling pathways triggering inflammation, autophagy and metabolic/trophic responses. Curr Med Chem 24:2261–2275. https://doi.org/10.2174/0929867324666170303161659
Park JH, Williams DR, Lee JH et al (2016) Potent suppressive effects of 1-Piperidinylimidazole based novel P2X7 receptor antagonists on cancer cell migration and invasion. J Med Chem 59:7410–7430. https://doi.org/10.1021/acs.jmedchem.5b01690
Pegoraro A, Bortolotti D, Marci R et al (2020) The P2X7 receptor 489C>T gain of function polymorphism favors HHV-6a infection and associates with female idiopathic infertility. Front Pharmacol 11:96. https://doi.org/10.3389/fphar.2020.00096
Pellegatti P, Raffaghello L, Bianchi G et al (2008) Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS ONE 3:e2599. https://doi.org/10.1371/journal.pone.0002599
Qian Y, Wang X, Li Y et al (2016) Extracellular ATP a new player in cancer metabolism: NSCLC cells internalize ATP in vitro and in vivo using multiple endocytic mechanisms. Mol Cancer Res 14:1087–1096. https://doi.org/10.1158/1541-7786.MCR-16-0118
Qian Y, Wang X, Liu Y et al (2014) Extracellular ATP is internalized by macropinocytosis and induces intracellular ATP increase and drug resistance in cancer cells. Cancer Lett 351:242–251. https://doi.org/10.1016/j.canlet.2014.06.008
Qian F, **ao J, Hu B et al (2017) High expression of P2X7R is an independent postoperative indicator of poor prognosis in colorectal cancer. Hum Pathol 64:61–68. https://doi.org/10.1016/j.humpath.2017.03.019
Qiu Y, Li WH, Zhang HQ et al (2014) P2X7 mediates ATP-driven invasiveness in prostate cancer cells. PLoS ONE 9:e114371. https://doi.org/10.1371/journal.pone.0114371
Raffaghello L, Chiozzi P, Falzoni S et al (2006) The P2X7 receptor sustains the growth of human neuroblastoma cells through a substance P-dependent mechanism. Cancer Res 66:907–914. https://doi.org/10.1158/0008-5472.CAN-05-3185
Reuzel PG, Arts JH, Lomax LG et al (1994) Chronic inhalation toxicity and carcinogenicity study of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats. Fundam Appl Toxicol 22:195–210. https://doi.org/10.1006/faat.1994.1024
Ribeiro DE, Roncalho AL, Glaser T et al (2019) P2X7 receptor signaling in stress and depression. Int J Mol Sci 20:2778. https://doi.org/10.3390/ijms20112778
Riteau N, Gasse P, Fauconnier L et al (2010) Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am J Respir Crit Care Med 182:774–783. https://doi.org/10.1164/rccm.201003-0359OC
Roger S, Jelassi B, Couillin I et al (2015) Understanding the roles of the P2X7 receptor in solid tumour progression and therapeutic perspectives. Biochim Biophys Acta 1848:2584–2602. https://doi.org/10.1016/j.bbamem.2014.10.029
Saito M, Kage H, Ando T et al (2019) Prevalence of bone pain decreases as lymph node stage increases in nonsmall cell lung cancer patients. Curr Probl Cancer 43:86–91. https://doi.org/10.1016/j.currproblcancer.2018.08.006
Salaro E, Rambaldi A, Falzoni S et al (2016) Involvement of the P2X7-NLRP3 axis in leukemic cell proliferation and death. Sci Rep 6:26280. https://doi.org/10.1038/srep26280
Salvestrini V, Orecchioni S, Talarico G et al (2017) Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells. Oncotarget 8:5895–5908. https://doi.org/10.18632/oncotarget.13927
Savio LEB, de Andrade MP, da Silva CG et al (2018) The P2X7 receptor in inflammatory diseases: angel or demon? Front Pharmacol 9:52. https://doi.org/10.3389/fphar.2018.00052
Schmid S, Kübler M, Korcan Ayata C et al (2015) Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer. Lung Cancer 90:516–521. https://doi.org/10.1016/j.lungcan.2015.10.005
Schneider G, Glaser T, Lameu C et al (2015) Extracellular nucleotides as novel, underappreciated pro-metastatic factors that stimulate purinergic signaling in human lung cancer cells. Mol Cancer 14:201. https://doi.org/10.1186/s12943-015-0469-z
Shemon AN, Sluyter R, Fernando SL et al (2006) A Thr357 to Ser polymorphism in homozygous and compound heterozygous subjects causes absent or reduced P2X7 function and impairs ATP-induced mycobacterial killing by macrophages. J Biol Chem 281:2079–2086. https://doi.org/10.1074/jbc.M507816200
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69:7–34. https://doi.org/10.3322/caac.21551
Singh N, Baby D, Rajguru JP et al (2019) Inflammation and cancer. Ann Afr Med 18:121–126. https://doi.org/10.4103/aam.aam_56_18
Singla N, Gupta D, Joshi A et al (2012) Genetic polymorphisms in the P2X7 gene and its association with susceptibility to tuberculosis. Int J Tuberc Lung Dis 16:224–229. https://doi.org/10.5588/ijtld.11.0076
Slater M, Danieletto S, Gidley-Baird A et al (2004) Early prostate cancer detected using expression of non-functional cytolytic P2X7 receptors. Histopathology 44:206–215. https://doi.org/10.1111/j.0309-0167.2004.01798.x
Sluyter R (2017) The P2X7 receptor. Adv Exp Med Biol 1051:17–53. https://doi.org/10.1007/5584_2017_59
Smart ML, Gu B, Panchal RG et al (2003) P2X7 receptor cell surface expression and cytolytic pore formation are regulated by a distal C-terminal region. J Biol Chem 278:8853–8860. https://doi.org/10.1074/jbc.M211094200
Solini A, Cuccato S, Ferrari D et al (2008) Increased P2X7 receptor expression and function in thyroid papillary cancer: a new potential marker of the disease? Endocrinology 149:389–396. https://doi.org/10.1210/en.2007-1223
Song S, Jacobson KN, McDermott KM et al (2016) ATP promotes cell survival via regulation of cytosolic [Ca2+] and Bcl-2/Bax ratio in lung cancer cells. Am J Physiol Cell Physiol 310:C99–114. https://doi.org/10.1152/ajpcell.00092.2015
Souza CO, Santoro GF, Figliuolo VR et al (2012) Extracellular ATP induces cell death in human intestinal epithelial cells. Biochim Biophys Acta 1820:1867–1878. https://doi.org/10.1016/j.bbagen.2012.08.013
Stemmer KL, Bingham E, Barkley W (1975) Pulmonary response to polyurethane dust. Environ Health Perspect 11:109–113. https://doi.org/10.1289/ehp.7511109
Surprenant A, Rassendren F, Kawashima E et al (1996) The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272:735–738. https://doi.org/10.1126/science.272.5262.735
Tafani M, Schito L, Pellegrini L et al (2011) Hypoxia-increased RAGE and P2X7R expression regulates tumor cell invasion through phosphorylation of Erk1/2 and Akt and nuclear translocation of NF-{kappa}B. Carcinogenesis 32:1167–1175. https://doi.org/10.1093/carcin/bgr101
Takai E, Tsukimoto M, Harada H et al (2012) Autocrine regulation of TGF-β1-induced cell migration by exocytosis of ATP and activation of P2 receptors in human lung cancer cells. J Cell Sci 125:5051–5060. https://doi.org/10.1242/jcs.104976
Takai E, Tsukimoto M, Harada H et al (2014) Autocrine signaling via release of ATP and activation of P2X7 receptor influences motile activity of human lung cancer cells. Purinergic Signal 10:487–497. https://doi.org/10.1007/s11302-014-9411-x
Tamajusuku AS, Villodre ES, Paulus R et al (2010) Characterization of ATP-induced cell death in the GL261 mouse glioma. J Cell Biochem 109:983–991. https://doi.org/10.1002/jcb.22478
Vacchelli E, Galluzzi L, Rousseau V et al (2012) Loss-of-function alleles of P2RX7 and TLR4 fail to affect the response to chemotherapy in non-small cell lung cancer. Oncoimmunology 1:271–278. https://doi.org/10.4161/onci.18684
Vereczkei A, Abdul-Rahman O, Halmai Z et al (2019) Association of purinergic receptor P2RX7 gene polymorphisms with depression symptoms. Prog Neuropsychopharmacol Biol Psychiatry 92:207–216. https://doi.org/10.1016/j.pnpbp.2019.01.006
Wang X, Li Y, Qian Y et al (2017) Extracellular ATP, as an energy and phosphorylating molecule, induces different types of drug resistances in cancer cells through ATP internalization and intracellular ATP level increase. Oncotarget 8:87860–87877. https://doi.org/10.18632/oncotarget.21231
Wang Q, Wang L, Feng YH et al (2004) P2X7 receptor-mediated apoptosis of human cervical epithelial cells. Am J Physiol Cell Physiol 287:C1349–C1358. https://doi.org/10.1152/ajpcell.00256.2004
Wesselius A, Bours MJ, Arts IC et al (2012) The P2X(7) loss-of-function Glu496Ala polymorphism affects ex vivo cytokine release and protects against the cytotoxic effects of high ATP-levels. BMC Immunol 13:64. https://doi.org/10.1186/1471-2172-13-64
White N, Butler PE, Burnstock G (2005) Human melanomas express functional P2X(7) receptors. Cell Tissue Res 321:411–418. https://doi.org/10.1007/s00441-005-1149-x
Wiley JS, Dao-Ung LP, Li C et al (2003) An Ile-568 to Asn polymorphism prevents normal trafficking and function of the human P2X7 receptor. J Biol Chem 278:17108–17113. https://doi.org/10.1074/jbc.M212759200
**a J, Yu X, Tang L et al (2015) P2X7 receptor stimulates breast cancer cell invasion and migration via the AKT pathway. Oncol Rep 34:103–110. https://doi.org/10.3892/or.2015.3979
Xu S, Shi L (2019) High expression of miR-155 and miR-21 in the recurrence or metastasis of non-small cell lung cancer. Oncol Lett 18:758–763. https://doi.org/10.3892/ol.2019.10337
Yan J, Li XY, Roman Aguilera A et al (2020) Control of metastases via myeloid CD39 and NK cell effector function. Cancer Immunol Res 8:356–367. https://doi.org/10.1158/2326-6066.CIR-19-0749
Yang YC, Chang TY, Chen TC et al (2016) Functional variant of the P2X7 receptor gene is associated with human papillomavirus-16 positive cervical squamous cell carcinoma. Oncotarget 7:82798–82803. https://doi.org/10.18632/oncotarget.12636
Yin QW, Sun XF, Yang GT et al (2015) Increased expression of microRNA-150 is associated with poor prognosis in non-small cell lung cancer. Int J Clin Exp Pathol 8:842–846
Young CNJ, Górecki DC (2018) P2RX7 purinoceptor as a therapeutic target-the second coming? Front Chem 6:248. https://doi.org/10.3389/fchem.2018.00248
Zhang Y, Ding J, Wang L (2019) The role of P2X7 receptor in prognosis and metastasis of colorectal cancer. Adv Med Sci 64:388–394. https://doi.org/10.1016/j.advms.2019.05.002
Zhang WJ, Hu CG, Zhu ZM et al (2020) Effect of P2X7 receptor on tumorigenesis and its pharmacological properties. Biomed Pharmacother 125:109844. https://doi.org/10.1016/j.biopha.2020.109844
Zhao X, Liu HZ, Zhang YQ (2016) Effect of P2X7 receptor knock-out on bone cancer pain in mice. Sheng Li Xue Bao 68:224–232
Zheng X, Li T, Chen Y et al (2017) Genetic polymorphisms of the P2X7 gene associated with susceptibility to and prognosis of pulmonary tuberculosis. Infect Genet Evol 53:24–29. https://doi.org/10.1016/j.meegid.2017.05.003
Zheng L, Zhang X, Yang F et al (2014) Regulation of the P2X7R by microRNA-216b in human breast cancer. Biochem Biophys Res Commun 452:197–204. https://doi.org/10.1016/j.bbrc.2014.07.101
Zhou L, Qi X, Potashkin JA et al (2008) MicroRNAs miR-186 and miR-150 down-regulate expression of the pro-apoptotic purinergic P2X7 receptor by activation of instability sites at the 3'-untranslated region of the gene that decrease steady-state levels of the transcript. J Biol Chem 283:28274–28286. https://doi.org/10.1074/jbc.M802663200
Zou J, Vetreno RP, Crews FT (2012) ATP-P2X7 receptor signaling controls basal and TNFα-stimulated glial cell proliferation. Glia 60:661–673. https://doi.org/10.1002/glia.22302
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This work was supported by the National Natural Science Foundation of China (no. 81770915 and 81301737) and the Major Program of Shandong Province Natural Science Foundation (no. ZR2018ZC1054).
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Li, Q., Zhu, X., Song, W. et al. The P2X7 purinergic receptor: a potential therapeutic target for lung cancer. J Cancer Res Clin Oncol 146, 2731–2741 (2020). https://doi.org/10.1007/s00432-020-03379-4
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DOI: https://doi.org/10.1007/s00432-020-03379-4