EGF/EGFR Promotes Salivary Adenoid Cystic Carcinoma Cell Malignant
Neural Invasion via Activation of PI3K/AKT and MEK/ERK Signaling

doi:10.2174/1568009622666220411112312

摘要

背景：涎腺腺样囊性癌（SACC）是涎腺最常见的恶性肿瘤之一，32.4-72.0%的SACC病例表现为神经浸润（NI）；然而，SACC高侵袭潜能的分子机制仍不清楚。方法: 本研究使用EGFR、PI3K和MEK抑制剂研究了表皮生长因子受体（EGFR）在AKT抑制或有丝分裂原激活蛋白激酶激酶（MEK）诱导的SACC细胞NI和上皮间充质转化（EMT）中的作用。使用MTT法评估SACC-83细胞存活率，并进行伤口愈合试验以评估细胞迁移。用链霉亲和素过氧化物酶免疫组化染色检测EMT、AKT、磷酸化（p）-AKT、ERK和p-ERK蛋白的阳性表达率。在裸鼠异种移植模型中，研究了EGFR、PI3K和MEK抑制剂对肿瘤生长和NI的影响。结果: EGF和EGFR在增加细胞存活、迁移和侵袭方面是有效的。SACC转移受PI3K/AKT和MEK/ERK途径的影响，这两种途径均由EGF/EGFR启动。EMT和NI由EGF/EGFR、PI3K/AKT和MEK/ERK途径调节。本研究结果证明了通过体外神经肿瘤共培养抑制SACC中NI中EGFR/AKT/MEK信号的重要性。此外，我们的临床前实验提供了确凿的证据，证明注射EGFR、PI3K和MEK抑制剂可抑制裸鼠SACC细胞的肿瘤生长和NI。结论: 经鉴定，EGFR、PI3K/AKT或MEK/ERK的抑制剂通过下调PI3K/AKT或MEK/ERK途径抑制SACC-83细胞的增殖、迁移和NI。还证明，抑制EGFR通过抑制PI3K/AKT和MEK/ERK的信号传导，消除SACC中的EMT。目前的结果表明靶向与EGF/EGFR下游通路相关的多种癌基因的潜在有效性，以及通过PI3K/AKT或MEK/ERK抑制限制SACC中NI的潜在治疗靶点。

关键词: EGF/EGFR通路、PI3K/AKT通路、MEK/ERK通路、涎腺腺样囊性癌、神经侵袭、治疗靶点。

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[1] 
Weng, L.X.; Wang, G.H.; Yao, H.; Yu, M.F.; Lin, J. Epigallocatechin gallate inhibits the growth of salivary adenoid cystic carcinoma cells via the EGFR/Erk signal transduction pathway and the mitochondria apoptosis pathway. Neoplasma,  2017, 64(4), 563-570.
[http://dx.doi.org/10.4149/neo_2017_410] [PMID: 28485162] 
[2] 
Xu, B.; Drill, E.; Ho, A.; Ho, A.; Dunn, L.; Prieto-Granada, C.N.; Chan, T.; Ganly, I.; Ghossein, R.; Katabi, N. Predictors of outcome in adenoid cystic carcinoma of salivary glands: A clinicopathologic study with correlation between MYB fusion and protein expression. Am. J. Surg. Pathol.,  2017, 41(10), 1422-1432.
[http://dx.doi.org/10.1097/PAS.0000000000000918] [PMID: 28719465] 
[3] 
Jang, S.; Patel, P.N.; Kimple, R.J.; McCulloch, T.M. Clinical outcomes and prognostic factors of adenoid cystic carcinoma of the head and neck. Anticancer Res.,  2017, 37(6), 3045-3052.
[PMID: 28551643] 
[4] 
Dai, W.; Yao, Y.; Zhou, Q.; Sun, C.F. Ubiquitin-specific peptidase 22, a histone deubiquitinating enzyme, is a novel poor prognostic factor for salivary adenoid cystic carcinoma. PLoS One,  2014, 9(1)e87148
[http://dx.doi.org/10.1371/journal.pone.0087148] [PMID: 24466336] 
[5] 
Xu, P.; Wang, S.; Luo, Y.; Yin, J.; Belkacemi, Y.; Lu, S.; Feng, M.; Lang, J. Outcome of adenoid cystic carcinoma of head and neck after postoperative intensity modulation radiotherapy: A single institution study. Cancer Manag. Res.,  2021, 13, 2411-2417.
[http://dx.doi.org/10.2147/CMAR.S283494] [PMID: 33758540] 
[6] 
Shang, J.; Sheng, L.; Wang, K.; Shui, Y.; Wei, Q. Expression of neural cell adhesion molecule in salivary adenoid cystic carcinoma and its correlation with perineural invasion. Oncol. Rep.,  2007, 18(6), 1413-1416.
[http://dx.doi.org/10.3892/or.18.6.1413] [PMID: 17982624] 
[7] 
Nomura, A.; Majumder, K.; Giri, B.; Dauer, P.; Dudeja, V.; Roy, S.; Banerjee, S.; Saluja, A.K. Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer. Lab. Invest.,  2016, 96(12), 1268-1278.
[http://dx.doi.org/10.1038/labinvest.2016.109] [PMID: 27775688] 
[8] 
Li, M.; Mukasa, A.; Inda, M.M.; Zhang, J.; Chin, L.; Cavenee, W.; Furnari, F. Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma. J. Exp. Med.,  2011, 208(13), 2657-2673.
[http://dx.doi.org/10.1084/jem.20111102] [PMID: 22162832] 
[9] 
Tabunoki, H.; Saito, N.; Suwanborirux, K.; Charupant, K.; Satoh, J. Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4-tetrahydroisoquinoline alkaloids. Cancer Cell Int.,  2012, 12(1), 14.
[http://dx.doi.org/10.1186/1475-2867-12-14] [PMID: 22494416] 
[10] 
Liu, Z.; Jiang, Z.; Huang, J.; Huang, S.; Li, Y.; Yu, S.; Yu, S.; Liu, X. miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. Int. J. Oncol.,  2014, 44(5), 1571-1580.
[http://dx.doi.org/10.3892/ijo.2014.2322] [PMID: 24603851] 
[11] 
Cantley, L.C. The phosphoinositide 3-kinase pathway. Science,  2002, 296(5573), 1655-1657.
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186] 
[12] 
Chang, F.; Lee, J.T.; Navolanic, P.M.; Steelman, L.S.; Shelton, J.G.; Blalock, W.L.; Franklin, R.A.; McCubrey, J.A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia,  2003, 17(3), 590-603.
[http://dx.doi.org/10.1038/sj.leu.2402824] [PMID: 12646949] 
[13] 
Moule, S.K.; Welsh, G.I.; Edgell, N.J.; Foulstone, E.J.; Proud, C.G.; Denton, R.M. Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells. Activation of protein kinase B by wortmannin-sensitive and -insensitive mechanisms. J. Biol. Chem.,  1997, 272(12), 7713-7719.
[http://dx.doi.org/10.1074/jbc.272.12.7713] [PMID: 9065430] 
[14] 
Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol.,  2002, 4(9), 648-657.
[http://dx.doi.org/10.1038/ncb839] [PMID: 12172553] 
[15] 
Clarke, J.; Butowski, N.; Chang, S. Recent advances in therapy for glioblastoma. Arch. Neurol.,  2010, 67(3), 279-283.
[http://dx.doi.org/10.1001/archneurol.2010.5] [PMID: 20212224] 
[16] 
Yang, W.; Xia, Y.; Cao, Y.; Zheng, Y.; Bu, W.; Zhang, L.; You, M.J.; Koh, M.Y.; Cote, G.; Aldape, K.; Li, Y.; Verma, I.M.; Chiao, P.J.; Lu, Z. EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol. Cell,  2012, 48(5), 771-784.
[http://dx.doi.org/10.1016/j.molcel.2012.09.028] [PMID: 23123196] 
[17] 
Tan, X.; Egami, H.; Ishikawa, S.; Kurizaki, T.; Tamori, Y.; Takai, E.; Hirota, M.; Ogawa, M. Relationship between the expression of extracellular signal-regulated kinase 1/2 and the dissociation of pancreatic cancer cells: Involvement of ERK1/2 in the dissociation status of cancer cells. Int. J. Oncol.,  2004, 24(4), 815-820.
[http://dx.doi.org/10.3892/ijo.24.4.815] [PMID: 15010817] 
[18] 
Du, W.; Pang, C.; Xue, Y.; Zhang, Q.; Wei, X. Dihydroartemisinin inhibits the Raf/ERK/MEK and PI3K/AKT pathways in glioma cells. Oncol. Lett.,  2015, 10(5), 3266-3270.
[http://dx.doi.org/10.3892/ol.2015.3699] [PMID: 26722323] 
[19] 
Kudo-Saito, C.; Shirako, H.; Takeuchi, T.; Kawakami, Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell,  2009, 15(3), 195-206.
[http://dx.doi.org/10.1016/j.ccr.2009.01.023] [PMID: 19249678] 
[20] 
Maeda, M.; Johnson, K.R.; Wheelock, M.J. Cadherin switching: Essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition. J. Cell Sci.,  2005, 118(Pt 5), 873-887.
[http://dx.doi.org/10.1242/jcs.01634] [PMID: 15713751] 
[21] 
Voulgari, A.; Pintzas, A. Epithelial-mesenchymal transition in cancer metastasis: Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim. Biophys. Acta,  2009, 1796(2), 75-90.
[PMID: 19306912] 
[22] 
Roberts, P.J.; Der, C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene,  2007, 26(22), 3291-3310.
[http://dx.doi.org/10.1038/sj.onc.1210422] [PMID: 17496923] 
[23] 
Hu, K.; Li, S.L.; Gan, Y.H.; Wang, C.Y.; Yu, G.Y. Epiregulin promotes migration and invasion of salivary adenoid cystic carcinoma cell line SACC-83 through activation of ERK and Akt. Oral Oncol.,  2009, 45(2), 156-163.
[http://dx.doi.org/10.1016/j.oraloncology.2008.04.009] [PMID: 18620900] 
[24] 
Wu, D.M.; Zhao, D.; Li, D.Z.; Xu, D.Y.; Chu, W.F.; Wang, X.F. Maslinic acid induces apoptosis in salivary gland adenoid cystic carcinoma cells by Ca2+-evoked p38 signaling pathway. Naunyn Schmiedebergs Arch. Pharmacol.,  2011, 383(3), 321-330.
[http://dx.doi.org/10.1007/s00210-011-0598-x] [PMID: 21279332] 
[25] 
Hu, J.A.; Li, Y.; Fang, J. Effect of ERK inhibitor on pulmonary metastasis of inoculated human adenoid cystic carcinoma cells in nude mice. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod.,  2010, 109(1), 117-123.
[http://dx.doi.org/10.1016/j.tripleo.2009.07.052] [PMID: 20123382] 
[26] 
Bouaichi, A.; Aimad-Eddine, S.; Mommers, X.A.; Ella, B.; Zwetyenga, N. Intra-mandibular adenoid cystic carcinoma. Rev. Stomatol. Chir. Maxillofac. Chir. Orale,  2014, 115(2), 100-104.
[PMID: 24674932] 
[27] 
Tagliamento, M.; Rijavec, E.; Barletta, G.; Biello, F.; Rossi, G.; Grossi, F.; Genova, C. CIMAvax-EGF, a therapeutic non-small cell lung cancer vaccine. Expert Opin. Biol. Ther.,  2018, 18(7), 829-835.
[http://dx.doi.org/10.1080/14712598.2018.1492539] [PMID: 29936901] 
[28] 
Hickey, K.; Grehan, D.; Reid, I.M.; O’Briain, S.; Walsh, T.N.; Hennessy, T.P. Expression of epidermal growth factor receptor and proliferating cell nuclear antigen predicts response of esophageal squamous cell carcinoma to chemoradiotherapy. Cancer,  1994, 74(6), 1693-1698.
[http://dx.doi.org/10.1002/1097-0142(19940915)74:6<1693:AID-CNCR2820740609>3.0.CO;2-#] [PMID: 7915963] 
[29] 
Ding, Z.; Roos, A.; Kloss, J.; Dhruv, H.; Peng, S.; Pirrotte, P.; Eschbacher, J.M.; Tran, N.L.; Loftus, J.C. A novel signaling complex between TROY and EGFR mediates glioblastoma cell invasion. Mol. Cancer Res.,  2018, 16(2), 322-332.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0454] [PMID: 29117939] 
[30] 
McCarthy, S.A.; Samuels, M.L.; Pritchard, C.A.; Abraham, J.A.; McMahon, M. Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. Genes Dev.,  1995, 9(16), 1953-1964.
[http://dx.doi.org/10.1101/gad.9.16.1953] [PMID: 7649477] 
[31] 
Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B.; Antipin, Y.; Mitsiades, N.; Landers, T.; Dolgalev, I.; Major, J.E.; Wilson, M.; Socci, N.D.; Lash, A.E.; Heguy, A.; Eastham, J.A.; Scher, H.I.; Reuter, V.E.; Scardino, P.T.; Sander, C.; Sawyers, C.L.; Gerald, W.L. Integrative genomic profiling of human prostate cancer. Cancer Cell,  2010, 18(1), 11-22.
[http://dx.doi.org/10.1016/j.ccr.2010.05.026] [PMID: 20579941] 
[32] 
Danielsen, S.A.; Eide, P.W.; Nesbakken, A.; Guren, T.; Leithe, E.; Lothe, R.A. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim. Biophys. Acta,  2015, 1855(1), 104-121.
[PMID: 25450577] 
[33] 
Henderson, V.; Smith, B.; Burton, L.J.; Randle, D.; Morris, M.; Odero-Marah, V.A. Snail promotes cell migration through PI3K/AKT-dependent Rac1 activation as well as PI3K/AKT-independent pathways during prostate cancer progression. Cell Adhes. Migr.,  2015, 9(4), 255-264.
[http://dx.doi.org/10.1080/19336918.2015.1013383] [PMID: 26207671] 
[34] 
Wykosky, J.; Hu, J.; Gomez, G.G.; Taylor, T.; Villa, G.R.; Pizzo, D.; VandenBerg, S.R.; Thorne, A.H.; Chen, C.C.; Mischel, P.S.; Gonias, S.L.; Cavenee, W.K.; Furnari, F.B. A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma. Cancer Res.,  2015, 75(2), 394-404.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-2004] [PMID: 25432173] 
[35] 
Pi, J.; Jiang, J.; Cai, H.; Yang, F.; Jin, H.; Yang, P.; Cai, J.; Chen, Z.W. GE11 peptide conjugated selenium nanoparticles for EGFR targeted oridonin delivery to achieve enhanced anticancer efficacy by inhibiting EGFR-mediated PI3K/AKT and Ras/Raf/MEK/ERK pathways. Drug Deliv.,  2017, 24(1), 1549-1564.
[http://dx.doi.org/10.1080/10717544.2017.1386729] [PMID: 29019267] 
[36] 
Hoeflich, K.P.; O’Brien, C.; Boyd, Z.; Cavet, G.; Guerrero, S.; Jung, K.; Januario, T.; Savage, H.; Punnoose, E.; Truong, T.; Zhou, W.; Berry, L.; Murray, L.; Amler, L.; Belvin, M.; Friedman, L.S.; Lackner, M.R. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin. Cancer Res.,  2009, 15(14), 4649-4664.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0317] [PMID: 19567590] 
[37] 
Mirzoeva, O.K.; Das, D.; Heiser, L.M.; Bhattacharya, S.; Siwak, D.; Gendelman, R.; Bayani, N.; Wang, N.J.; Neve, R.M.; Guan, Y.; Hu, Z.; Knight, Z.; Feiler, H.S.; Gascard, P.; Parvin, B.; Spellman, P.T.; Shokat, K.M.; Wyrobek, A.J.; Bissell, M.J.; McCormick, F.; Kuo, W.L.; Mills, G.B.; Gray, J.W.; Korn, W.M. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res.,  2009, 69(2), 565-572.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3389] [PMID: 19147570] 
[38] 
Alessi, D.R.; Cuenda, A.; Cohen, P.; Dudley, D.T.; Saltiel, A.R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem.,  1995, 270(46), 27489-27494.
[http://dx.doi.org/10.1074/jbc.270.46.27489] [PMID: 7499206] 
[39] 
Sheppard, K.E.; Cullinane, C.; Hannan, K.M.; Wall, M.; Chan, J.; Barber, F.; Foo, J.; Cameron, D.; Neilsen, A.; Ng, P.; Ellul, J.; Kleinschmidt, M.; Kinross, K.M.; Bowtell, D.D.; Christensen, J.G.; Hicks, R.J.; Johnstone, R. W.; McArthur, G.A.; Hannan, R.D.; Phillips, W.A.; Pearson, R.B. Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur. J. Cancer. (Oxford, England: 1990),  2013, 49(18), 3936-3944.
[40] 
Wang, Y.; Hu, J.; Wang, Y.; Ye, W.; Zhang, X.; Ju, H.; Xu, D.; Liu, L.; Ye, D.; Zhang, L.; Zhu, D.; Deng, J.; Zhang, Z.; Liu, S. EGFR activation induced Snail-dependent EMT and myc-dependent PD-L1 in human salivary adenoid cystic carcinoma cells. Cell Cycle,  2018, 17(12), 1457-1470.
[http://dx.doi.org/10.1080/15384101.2018.1489177] [PMID: 29954240] 

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DOI https://dx.doi.org/10.2174/1568009622666220411112312	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576

当代肿瘤药物靶点

EGF/EGFR通过激活PI3K/AKT和MEK/ERK信号促进涎腺腺样囊性癌细胞恶性神经侵袭

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当代肿瘤药物靶点

EGF/EGFR通过激活PI3K/AKT和MEK/ERK信号促进涎腺腺样囊性癌细胞恶性神经侵袭

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