钠氢交换体1在肿瘤微环境中的作用

doi:10.3760/cma.j.issn.1673422X.2017.03.012

摘要/Abstract

摘要： 由于细胞外酸化和细胞内碱化造成的细胞内外pH值梯度的反转是肿瘤代谢微环境的一个重要特征。钠氢交换体1（NHE1）广泛存在于各种细胞的细胞膜上，并在调节细胞内外酸碱平衡及细胞体积中起重要作用。NHE1对肿瘤微环境具有调控作用，并参与恶性肿瘤的侵袭和迁移，可能成为抗肿瘤治疗潜在的新靶点。

关键词: 酸碱平衡, 肿瘤浸润, 细胞运动, 肿瘤微环境, 钠氢交换体1

Abstract: The reversed pH gradient across the cell membrane on account of intracellular alkalinization and extracellular acidosis is an importart characteristic of tumor microenvironment. Sodium hydrogen exchanger isoform 1 (NHE1) is ubiquitously expressed at the plasma membrane of many types of cells, which plays a critical role in intracellular pH and cell volume homeostasis. NHE1 plays an important role in the regulation of tumor microenvironment and involves in tumor migration and invasion, which may be a potential new target in anticancer therapy.

Key words: Acidbase equilibrium, Neoplasm invasiveness, Cell movement, Tumor microenvironment, Sodium hydrogen exchanger isoform 1

王伟,杨学军. 钠氢交换体1在肿瘤微环境中的作用[J]. 国际肿瘤学杂志, 2017, 44(3): 205-208.

Wang Wei, Yang Xuejun. Role of sodium hydrogen exchanger isoform 1 in tumor microenvironment[J]. Journal of International Oncology, 2017, 44(3): 205-208.

参考文献

［1］ Parks SK, Chiche J, Pouysségur J. Disrupting proton dynamics and energy metabolism for cancer therapy［J］. Nat Rev Cancer, 2013, 13(9): 611 -623. DOI: 10.1038/nrc3579. ［2］ Webb BA, Chimenti M, Jacobson MP, et al. Dysregulated pH: a perfect storm for cancer progression［J］. Nat Rev Cancer, 2011, 11(9): 671-677. DOI: 10.1038/nrc3110. ［3］ Cong D, Zhu W, Kuo JS, et al. Ion transporters in brain tumors［J］. Curr Med Chem, 2015, 22(10): 1171-1181. ［4］ Parker MD, Myers EJ, Schelling JR. Na+H+ exchanger1 (NHE1) regulation in kidney proximal tubule［J］. Cell Mol Life Sci, 2015, 72(11): 2061-2074. DOI: 10.1007/s0001801518488. ［5］ Amith SR, Fliegel L. Regulation of the Na+/H+ exchanger (NHE1) in breast cancer metastasis［J］. Cancer Res, 2013, 73(4): 1259-1264. DOI: 10.1158/00085472.CAN124031. ［6］ Xu J, Ji B, Wen G, et al. Na+/H+ exchanger 1, Na+/Ca2+ exchanger 1 and calmodulin complex regulates interleukin 6mediated cellular behavior of human hepatocellular carcinoma［J］. Carcinogenesis, 2016, 37(3): 290 -300. DOI: 10.1093/carcin/bgw004. ［7］ Matsushita M, Tanaka H, Mitsui K, et al. Dual functional significance of calcineurin homologous protein 1 binding to Na(+)/H(+) exchanger isoform 1［J］. Am J Physiol Cell Physiol, 2011, 301(2): C280-288. DOI: 10.1152/ajpcell.00404.2010. ［8］ Vargas LA, Díaz RG, Swenson ER, et al. Inhibition of carbonic anhydrase prevents the Na(+)/H(+) exchanger 1dependent slow force response to rat myocardial stretch［J］. Am J Physiol Heart Circ Physiol, 2013, 305(2): H228-237. DOI: 10.1152/ajpheart.00055.2013. ［9］ Beaty BT, Wang Y, BravoCordero JJ, et al. Talin regulates moesinNHE1 recruitment to invadopodia and promotes mammary tumor metastasis［J］. J Cell Biol, 2014, 205(5): 737-751. DOI: 10.1083/jcb.201312046. ［10］ Fuster DG, Alexander RT. Traditional and emerging roles for the SLC9 Na+/H+ exchangers［J］. Pflugers Arch, 2014, 466(1): 61-76. DOI: 10.1007/s0042401314088. ［11］ Rose KL, Watson AJ, Drysdale TA, et al. Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodiumhydrogen exchange and anion transport［J］. Am J Physiol Endocrinol Metab, 2015, 309(4): E370-379. DOI: 10.1152/ajpendo.00107.2015. ［12］ Yi YH, Chang YS, Lin CH, et al. Integrinmediated membrane blebbing is dependent on sodiumproton exchanger 1 and sodiumcalcium exchanger 1 activity［J］. J Biol Chem, 2012, 287(13): 10316-10324. DOI: 10.1074/jbc.M111.244962. ［13］ Chang G, Wang J, Zhang H, et al. CD44 targets Na(+)/H(+) exchanger 1 to mediate MDAMB231 cells′ metastasis via the regulation of ERK1/2［J ］. Br J Cancer, 2014, 110(4): 916-927. DOI: 10.1038/bjc.2013.809. ［14］ McGrail DJ, McAndrews KM, Brandenburg CP, et al. Osmotic regulation is required for cancer cell survival under solid stress［J］. Biophys J, 2015, 109(7): 1334-1337. DOI: 10.1016/j.bpj.2015.07.046. ［15］ Amith SR, Fong S, Baksh S, et al. Na(+)/H(+) exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis?［J］. Int J Dev Biol, 2015, 59(79): 367-377. DOI: 10.1387/ijdb.140336lf. ［16］ Liberti MV, Locasale JW. The Warburg Effect: how does it benefit cancer cells?［J］. Trends Biochem Sci, 2016, 41(3): 211-218. DOI: 10.1016/j.tibs.2015.12.001. ［17］ Reshkin SJ, Greco MR, Cardone RA. Role of pHi, and proton transporters in oncogenedriven neoplastic transformation［J］. Philos Trans R Soc Lond B Biol Sci, 2014, 369(1638): 20130100. DOI: 10.1098/rstb.2013.0100. ［18］ Yang X, Wang D, Dong W, et al. Overexpression of Na+/H+ exchanger 1 and its clinicopathologic significance in hepatocellular carcinoma［J］. Med Oncol, 2010, 27(4): 1109-1113. DOI: 10.1007/s1203200993434. ［19］ Xia J, Huang N, Huang H, et al. Voltagegated sodium channel Nav 1.7 promotes gastric cancer progression through MACC1mediated upregulation of NHE1［J］. Int J Cancer, 2016, 139(11): 2553-2569. DOI: 10.1002/ijc.30381. ［20］ Cardone RA, Greco MR, Zeeberg K, et al. A novel NHE1centered signaling cassette drives epidermal growth factor receptordependent pancreatic tumor metastasis and is a target for combination therapy［J］. Neoplasia, 2015, 17(2): 155-166. DOI: 10.1016/j.neo.2014.12.003. ［21］ Zhu W, Carney KE, Pigott VM, et al. Gliomamediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1［J］. Carcinogenesis, 2016, 37(9): 839-851. DOI: 10.1093/carcin/bgw068. ［22］朱蒙, 杨学军. 钙信号在恶性肿瘤侵袭迁移中的作用［J］. 国际肿瘤学杂志, 2014, 41(3): 161-164. DOI: 10.3760/cma.j.issn.1673422X.2014.03.001. ［23］ Lin Y, Chang G, Wang J, et al. NHE1 mediates MDAMB231 cells invasion through the regulation of MT1MMP［J］. Exp Cell Res, 2011, 317 (14): 2031-2040. DOI: 10.1016/j.yexcr.2011.05.026. ［24］ Provost JJ, Rastedt D, Canine J, et al. Urokinase plasminogen activator receptor induced nonsmall cell lung cancer invasion and metastasis requires NHE1 transporter expression and transport activity［J］ . Cell Oncol (Dordr), 2012, 35（2）： 95-110. DOI: 10.1007/s134020110068y. ［25］ Ludwig FT, Schwab A, Stock C. The Na+/H+ exchanger (NHE1) generates pH nanodomains at focal adhesions［J］. J Cell Physiol, 2013, 228(6): 1351-1358. DOI: 10.1002/jcp.24293. ［26］ Chang F, Minc N. Electrochemical control of cell and tissue polarity ［J］. Annu Rev Cell Dev Biol, 2014, 30: 317-336. DOI: 10.1146/annurevcellbio100913013357. ［27］ Wallert MA, Hammes D, Nguyen T, et al. RhoA Kinase (Rock) and p90 Ribosomal S6 Kinase (p90Rsk) phosphorylation of the sodium hydrogen exchanger (NHE1) is required for lysophosphatidic acidinduced transport, cytoskeletal organization and migration［J］. Cell Signal, 2015, 27(3): 498-509. DOI: 10.1016/j.cellsig.2015.01.002. ［28］ Magalhaes MA, Larson DR, Mader CC, et al. Cortactin phosphorylation regulates cell invasion through a pHdependent pathway［ J］. J Cell Biol, 2011, 195(5): 903-920. DOI: 10.1083/jcb.201103045. ［29］ Zhang S, Liu F, Mao X, et al. Elevation of miR27b by HPV16 E7 inhibits PPARγ expression and promotes proliferation and invasion in cervical carcinoma cells［J］. Int J Oncol, 2015, 47(5): 1759-1766. DOI: 10.3892/ijo.2015.3162. ［30］ Lin Y, Wang J, Jin W, et al. NHE1 mediates migration and invasion of HeLa cells via regulating the expression and localization of MT1MMP［J］. Cell Biochem Funct, 2012, 30(1): 41-46. DOI: 10.1002/cbf.1815. ［31］ Amith SR, Wilkinson JM, Fliegel L. Na+/H+ exchanger NHE1 regulation modulates metastatic potential and epithelialmesenchymal transition of triplenegative breast cancer cells［J］. Oncotarget, 2016, 7(16): 21091- 21113. DOI: 10.18632/oncotarget.8520. ［32］ Andersen AP, Flinck M, Oernbo EK, et al. Roles of acidextrudingion transporters in regulation of breast cancer cell growth in a 3dimensional microenvironment［J］. Mol Cancer, 2016, 15(1): 45. DOI: 10.1186/s1294301605280. ［33］ Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity［J］. Cell, 2011, 147(5): 992-1009. DOI: 10.1016/j.cell.2011.11.016. ［34］ Thompson EG, Sontheimer H. A role for ion channels in perivascular glioma invasion［J］. Eur Biophys J, 2016, 45(7): 635-648. DOI: 10.1007/s002490161154x.

[1]	傅旖, 马辰莺, 张露, 周菊英. 生境分析在恶性肿瘤影像组学中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(5): 292-297.
[2]	杨智, 陆以乔, 顾花艳, 丁佳玲, 郭贵龙. 肿瘤微环境介导乳腺癌靶向治疗耐药的研究进展[J]. 国际肿瘤学杂志, 2024, 51(4): 235-238.
[3]	刘筱迪, 苏剑飞, 张静娴, 卫雪芹, 贾英杰. 髓源性抑制细胞在肿瘤血管生成中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(1): 50-54.
[4]	顾花艳, 朱腾, 郭贵龙. 乳房微生物群与乳腺癌：现状与未来[J]. 国际肿瘤学杂志, 2024, 51(1): 55-58.
[5]	向玉玲, 谭佳杰, 熊远果, 赵丽蓉, 黎晨, 张洪. 脱水淫羊藿素对肝癌细胞增殖、迁移和凋亡的影响[J]. 国际肿瘤学杂志, 2023, 50(9): 513-519.
[6]	许萌, 姜伟, 朱海涛, 曹雄锋. 癌相关成纤维细胞在肿瘤放疗抵抗中的研究进展[J]. 国际肿瘤学杂志, 2023, 50(4): 227-230.
[7]	丁浩, 应劲涛, 付茂勇. CAR-T在食管鳞状细胞癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2023, 50(4): 231-235.
[8]	曹梦清, 徐志勇, 施毓婷, 王凯. 三级淋巴结构在肿瘤免疫微环境调节和抗肿瘤治疗中的作用[J]. 国际肿瘤学杂志, 2023, 50(3): 169-173.
[9]	徐良富, 李袁飞. MSS型结直肠癌肿瘤微环境及免疫联合治疗研究进展[J]. 国际肿瘤学杂志, 2023, 50(3): 186-190.
[10]	朱易, 陈健. 硫化氢在肿瘤发生发展中的作用机制及其供体抗肿瘤作用[J]. 国际肿瘤学杂志, 2023, 50(12): 729-733.
[11]	谢露露, 丁江华. 免疫治疗在晚期三阴性乳腺癌中的应用进展[J]. 国际肿瘤学杂志, 2023, 50(11): 672-676.
[12]	陶红, 殷红, 罗宏, 陶佳瑜. 靶向肿瘤相关巨噬细胞增强结直肠癌免疫检查点抑制剂疗效的潜在策略[J]. 国际肿瘤学杂志, 2023, 50(11): 683-687.
[13]	马雪艳, 鲁历历, 孙鹏飞. 免疫微环境在宫颈癌中的研究进展[J]. 国际肿瘤学杂志, 2023, 50(1): 47-50.
[14]	吴嘉钰, 刘加成. 孤立性磨玻璃结节样肺腺癌的影像组学研究进展[J]. 国际肿瘤学杂志, 2022, 49(8): 449-452.
[15]	张子叔, 乌新林. 肿瘤微环境中乳酸的作用机制及相关治疗[J]. 国际肿瘤学杂志, 2022, 49(6): 349-352.