Role of EphA2 in pathogenesis of nasopharyngeal carcinoma and its potential as a therapeutic target
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摘要: 促红细胞生成素产生肝细胞受体（erythropoietin-producing hepatocellular receptor，Eph）及其配体ephrin，是最大受体酪氨酸激酶（RTK）家族，由于配体ephrin和Eph受体均结合在细胞膜上，激活的信号转导通路，一般发生在直接接触的细胞之间，具有双向信号转导的独特特点。Eph受体-ephrin配体导致排斥性细胞收缩反应在许多生理和病理过程中起重要作用，在16种Eph受体中，EphA2与肿瘤的联系最强，因此已被广泛研究。肿瘤细胞中的EphA2信号传导可能具有促进肿瘤或抑制肿瘤的作用，取决于肿瘤微环境，EphA2具有需要配体和激酶活性的经典信号，也具有不需要配体或激酶活性的非经典信号形式。本文就近年来Epha2在鼻咽癌致病过程中非受体依赖机制和作为EB病毒感染关键分子的作用及治疗靶点展望等研究进展进行综述，以期为鼻咽癌的预防和治疗提供新的思路。Abstract: The erythropoietin-producing hepatocellular receptor (Eph) and its ligand ephrin are the largest of the receptor tyrosine kinases (RTKs) family in humans. Since ephrin ligands and Eph receptors are membrane-bound proteins, binding and activation of Eph/ephrin intracellular signaling pathways can only occur via direct cell-cell interaction. Eph-ephrin complexes emanate bidirectional signals that affect cells expressing Eph and ephrin, respectively. Its repulsive signaling effects include retraction, which plays an important role in many physiological and pathological processes. EphA2 has been found to have a strong association with tumors and is most widely studied. EphA2 signal transduction in tumor cells may promote or inhibit tumor, depending on the tumor microenvironment. EphA2 "canonical" signaling involves ligand binding and kinase activity; thus EphA2 "noncanonical" signaling is ligand independent and lacks kinase activity. This review summarizes the pathogenesis of EphA2 in nasopharyngeal carcinoma (NPC), including ligand independent signal and EBV infection receptor, furthermore evaluates the prospect of its potential utilization as a target for cancer therapeutics. This may provide a new method for the prevention and treatment of NPC.
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[1] 中国抗癌协会肿瘤标志专业委员会鼻咽癌标志物专家委员会.鼻咽癌标志物临床应用专家共识[J].中国癌症防治杂志, 2019, 11(3):183-193. doi: 10.3969/j.issn.1674-5671.2019.03.01 [2] Chua MLK, Wee JTS, Hui EP, et al. Nasopharyngeal carcinoma[J]. Lancet, 2016, 387(10022):1012-1024. doi: 10.1016/S0140-6736(15)00055-0 [3] Hirai H, Maru Y, Hagiwara K, et al. A novel putative tyrosine kinase receptor encoded by the eph gene[J]. Science, 1987, 238:1717-1720. doi: 10.1126/science.2825356 [4] Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease[J]. Cell, 2008, 133(1):38-52. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=372496e0f55afa251a54f4767e954b01 [5] Anderson DJ, Barbacld M, Berg LJ, et al. Unified nomenclature for eph family receptors and their ligands, the Ephrins[J]. Cell, 1997, 90(3):403-404. https://www.cell.com/fulltext/S0092-8674(00)80500-0 [6] Lisabeth EM, Falivelli G, Pasquale EB. Eph receptor signaling and ephrins[J]. Cold Spring Harb Perspect Biol, 2013, 5(9):a009159. doi: 10.1101/cshperspect.a009159 [7] Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour[J]. Nat Rev Mol Cell Biol, 2005, 6(6):462-475. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=caf20a265285f8b271306855036ca751 [8] Ireton RC, Chen J. EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics[J]. Current Cancer Drug Targets, 2005, 5:149-157. doi: 10.2174/1568009053765780 [9] Wykosky J, Debinski W. The EphA2 receptor and ephrinA1 ligand in solid tumors:function and therapeutic targeting[J]. Mol Cancer Res, 2008, 6(12):1795-1806. doi: 10.1158/1541-7786.MCR-08-0244 [10] Tandon M, Vemula SV, Mittal SK. Emerging strategies for EphA2 receptor targeting for cancer therapeutics[J]. Review, 2011, 15(1):31-51. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016619/ [11] Pasquale EB. Eph receptors and ephrins in cancer:bidirectional signalling and beyond[J]. Nat Rev Cancer, 2010, 10(3):165-180. doi: 10.1038/nrc2806 [12] Beauchamp A, Debinski W. Ephs and ephrins in cancer:ephrin-A1 signalling[J]. Semin Cell Dev Biol, 2012, 23(1):109-115. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288643/ [13] Miao H, Wei BR, Peehl DM, et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway[J]. Nat Cell Biol, 2001, 3(5):527-530. doi: 10.1038/35074604 [14] Yang NY, Fernandez C, Richter M, et al. Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells[J]. Cell Signal, 2011, 23(1):201-212. doi: 10.1016/j.cellsig.2010.09.004 [15] Miao H, Li DQ, Mukherjee A, et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt[J]. Cancer Cell, 2009, 16(1):9-20. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=934375d011786f9751ec605f83c234e3 [16] Miao H, Gale NW, Guo H, et al. EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross-talk with Akt and regulates stem cell properties[J]. Oncogene, 2015, 34(5):558-567. doi: 10.1038/onc.2013.590 [17] Paraiso KH, Das Thakur M, Fang B, et al. Ligand-independent EPHA2 signaling drives the adoption of a targeted therapy-mediated metastatic melanoma phenotype[J]. Cancer Discov, 2015, 5(3):264-273. doi: 10.1158/2159-8290.CD-14-0293 [18] Petty A, Myshkin E, Qin H, et al. A small molecule agonist of EphA2 receptor tyrosine kinase inhibits tumor cell migration in vitro and prostate cancer metastasis in vivo[J]. PLoS One, 2012, 7(8):e42120. doi: 10.1371/journal.pone.0042120 [19] Koshikawa N, Hoshino D, Taniguchi H, et al. Proteolysis of EphA2 converts it from a tumor suppressor to an oncoprotein[J]. Cancer Res, 2015, 75(16):3327-3339. doi: 10.1158/0008-5472.CAN-14-2798 [20] Ieguchi K, Tomita T, Omori T, et al. ADAM12-cleaved ephrin-A1 contributes to lung metastasis[J]. Oncogene, 2014, 33(17):2179-2190. doi: 10.1038/onc.2013.180 [21] Li JY, Xiao T, Yi HM, et al. S897 phosphorylation of EphA2 is indispensable for EphA2-dependent nasopharyngeal carcinoma cell invasion, metastasis and stem properties[J]. Cancer Lett, 2019, 444:162-174. doi: 10.1016/j.canlet.2018.12.011 [22] Tan P, Liu Y, Yu C, et al. EphA2 silencing in nasopharyngeal carcinoma leads to decreased proliferation, invasion and increased sensitization to paclitaxel[J]. Oncol Lett, 2012, 4(3):429-434. doi: 10.3892/ol.2012.746 [23] Wang Y, Liu Y, Li G, et al. Ephrin typeA receptor 2 regulates sensitivity to paclitaxel in nasopharyngeal carcinoma via the phosphoinositide 3kinase/Akt signalling pathway[J]. Mol Med Rep, 2015, 11(2):924-930. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262504/ [24] 卢善翃, 王芸芸, 李果, 等.EphA2经P-糖蛋白调控鼻咽癌紫杉醇敏感性的实验研究[J].中国耳鼻咽喉颅底外科杂志, 2018, 1(24):33-38. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zgebyhldwkzz201801008 [25] Fingeroth JD, Weis JJ, Tedder TF, et al. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2[J]. Immunology, 1984, 81(14):4510-4514. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC345620/ [26] Mullen MM, Keith MH, Richard L, et al. Structure of the epstein-barr virus gp42 protein bound to the MHC class ⅢReceptor HLA-DR1[J]. Molecular Cell, 2002, 9(2):375-385. https://europepmc.org/article/MED/11864610 [27] Nemerow GR, Mold C, Schwend VK, et al. Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-barr virus (EBV) to the EBV/C3d receptor of B cells:sequence homology of gp350 and C3 complement fragment C3dt[J]. J Virol, 1987, 61(5):155-158. http://med.wanfangdata.com.cn/Paper/Detail/PeriodicalPaper_PM3033269 [28] Connolly SA, Jackson JO, Jardetzky TS, et al. Fusing structure and function:a structural view of the herpesvirus entry machinery[J]. Nat Rev Microbiol, 2011, 9(5):369-381. doi: 10.1038/nrmicro2548 [29] Ressing ME, Leeuwen DV, Verreck FAW, et al. Interference with T cell receptor-HLA-DR interactions by Epstein-Barr virus gp42 results in reduced T helper cell recognition[J]. Proc Natl Acad Sci U S A, 2003, 100(20):11583-1188. doi: 10.1073/pnas.2034960100 [30] Sathiyamoorthy K, Jiang J, Hu YX, et al. Assembly and architecture of the EBV B cell entry triggering complex[J]. PLoS Pathog, 2014, 10(8):e1004309. doi: 10.1371/journal.ppat.1004309 [31] Borza CM, Hutt-Fletcher LM. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus[J]. Nat Med, 2002, 8(6):594-599. doi: 10.1038/nm0602-594 [32] Kirschner AN, Omerovic J, Popov B, et al. Soluble Epstein-barr virus glycoproteins gH, gL, and gp42 form a 1:1:1 stable complex that acts like soluble gp42 in B-cell fusion but not in epithelial cell fusion[J]. J Virol, 2006, 80(19):9444-9454. doi: 10.1128/JVI.00572-06 [33] Turk SM, Jiang R, Chesnokova LS, et al. Antibodies to gp350/220 enhance the ability of Epstein-Barr virus to infect epithelial cells[J]. J Virol, 2006, 80(19):9628-9633. doi: 10.1128/JVI.00622-06 [34] Wang X, Kenyon WJ, Li Q, et al. Epstein-barr virus uses different complexes of glycoproteins gH and gL to infect B lymphocytes and epithelial cells[J]. J Virol, 1998, 72(7):109-119. http://med.wanfangdata.com.cn/viewHTML/PeriodicalPaper_JJ023319083.aspx [35] Chesnokova LS, Hutt-Fletcher LM. Fusion of epstein-barr virus with epithelial cells can be triggered by alphavbeta5 in addition to alphavbeta6 and alphavbeta8, and integrin binding triggers a conformational change in glycoproteins gHgL[J]. J Virol, 2011, 85(24):13214-13223. doi: 10.1128/JVI.05580-11 [36] Chesnokova LS, Nishimura SL, Hutt-Fletcher LM. Fusion of epithelial cells by Epstein-Barr virus proteins is triggered by binding of viral glycoproteins gHgL to integrins αvβ6 or αvβ8[J]. PNAS, 2009, 106(48):20464-20469. doi: 10.1073/pnas.0907508106 [37] Chen J, Sathiyamoorthy K, Zhang X, et al. Ephrin receptor A2 is a functional entry receptor for Epstein-Barr virus[J]. Nat Microbiol, 2018, 3(2):172-180. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=c93c8b7870a5c65a6037cca8ad6fc00a [38] Zhang H, Li Y, Wang HB, et al. Ephrin receptor A2 is an epithelial cell receptor for Epstein-barr virus entry[J]. Nat Microbiol, 2018, 3(2):1-8. https://scholars.houstonmethodist.org/en/publications/ephrin-receptor-a2-is-an-epithelial-cell-receptor-for-epsteinbarr-virus-entry(7760829d-12d7-45de-b2f0-4e868aebb8b6).html [39] Xiang T, Lin YX, Ma W, et al. Vasculogenic mimicry formation in EBVassociated epithelial malignancies[J]. Nat Commun, 2018, 9(1):5009. https://www.ncbi.nlm.nih.gov/pubmed/30479336 [40] Miao H, Li DQ, Mukherjee A, et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt[J]. Cancer Cell, 2009, 16(1):9-20. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=934375d011786f9751ec605f83c234e3 [41] Chang Q, Jorgensen C, Pawson T, et al. Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signalling in pancreatic cancer[J]. Br J Cancer, 2008, 99:1074-1082. doi: 10.1038/sj.bjc.6604676 [42] Wykosky J, Palma E, Gibo DM, et al. Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor[J]. Oncogene, 2008, 27(58):7260-7273. doi: 10.1038/onc.2008.328 [43] Koolpe M, Dail M, Pasquale EB. An ephrin mimetic peptide that selectively targets the EphA2 receptor[J]. J Biol Chem, 2002, 277(49):46974-46979. doi: 10.1074/jbc.M208495200 [44] Landen CN Jr, Lu C, Han LY, et al. Efficacy and antivascular effects of EphA2 reduction with an agonistic antibody in ovarian cancer[J]. J Natl Cancer Inst, 2006, 98(21):1558-1570. doi: 10.1093/jnci/djj414 [45] Coffman KT, Hu M, Carles-Kinch K, et al. Differential EphA2 epitope display on normal versus malignant cells[J]. Cancer Res, 2003, 63(22):7907-7912. https://www.ncbi.nlm.nih.gov/pubmed/14633720 [46] Alves PM, Faure O, Graff-Dubois S, et al. EphA2 as target of anticancer immunotherapy:identification of HLA-A*0201-restricted epitopes[J]. Cancer Res, 2003, 63(23):8476-8480. https://www.ncbi.nlm.nih.gov/pubmed/14679012 [47] Duxbury MS, Ito H, Zinner MJ, et al. EphA2:a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma[J]. Oncogene, 2004, 23(7):1448-1456. doi: 10.1038/sj.onc.1207247 [48] Wu B, Wang S, De SK, et al. Design and characterization of novel EphA2 agonists for targeted delivery of chemotherapy to cancer cells[J]. Chem Biol, 2015, 22(7):876-887. doi: 10.1016/j.chembiol.2015.06.011 [49] Lee JW, Han HD, Shahzad MMK, et al. EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma[J]. J Natl Cancer Inst, 2009, 101(17):1193-1205. doi: 10.1093/jnci/djp231 [50] Bennett G, Brown A, Mudd G, et al. MMAE delivery using the Bicycle toxin conjugate BT5528[J]. Mol Cancer Ther, 2020, 12:1092. https://mct.aacrjournals.org/content/molcanther/early/2020/05/09/1535-7163.MCT-19-1092.full.pdf -
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