Abstract
Purpose
Anion exchanger 1 (AE1) is a transmembrane glycoprotein which is abundantly expressed in erythrocyte plasma membrane and mediates the electroneutral exchange of Cl− and HCO3 −. We previously reported that the AE1 protein was unexpectedly expressed in the gastric and colonic cancer and take part in the carcinogenesis of the cancer cells. The aim of the present study is to determine the potential clinical implications of AE1 expression in gastric carcinoma.
Methods
Immunohistochemistry assay was used to determine the expression of AE1 protein. The expression of AE1 in normal and malignant tissues from 286 patients with early and advanced gastric carcinoma was examined. The correlations of AE1 expression with clinicopathological parameters, including age, tumor size, location and subtypes, expression frequency, survival period and lymph metastasis were assessed by Chi-squared test and t test analysis.
Results
AE1 immunoreactivity was negative in normal gastric tissue. Positive immunostaining of AE1 was detected in gastric carcinoma regardless of the location. AE1 was most frequently expressed in the gastric antrum carcinoma compared with gastric body cancer (P = 0.034). Expression of AE1 was significantly associated with bigger tumor size, deeper invasion, shorter survival period, and non-lymph metastasis. In para-cancer tissues of intestinal-type gastric cancer, the expression frequency of AE1 was higher than that in diffuse-type (P = 0.011).
Conclusion
The results showed a strong association of AE1 expression with the onset and progression of the gastric cancer and that may be helpful for improving the tumor classification and the treatment of cancer.
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References
Akel A, Wagner CA, Kovacikova J, Kasinathan RS, Kiedaisch V, Koka S, Alper SL, Bernhardt I, Wieder T, Huber SM, Lang F (2007) Enhanced suicidal death of erythrocytes from gene-targeted mice lacking the Cl−/HCO3 − exchanger AE1. Am J Physiol Cell Physiol 292(5):C1759–C1767. doi:10.1152/ajpcell.00158.2006
Alper SL (2006) Molecular physiology of SLC4 anion exchangers. Exp Physiol 91(1):153–161. doi:10.1113/expphysiol.2005.031765
Alper SL, Darman RB, Chernova MN, Dahl NK (2002) The AE gene family of Cl−/HCO3 − exchangers. J Nephrol 15:S41–S53
Argani P, Choti MA, Abraham SC (2007) Achlorhydria, parietal cell hyperplasia, and multiple gastric carcinoids: a new disorder. Am J Surg Pathol 31(3):488. doi:10.1097/01.pas.0000213405.95440.a1
Argent RH, Thomas RJ, Aviles-Jimenez F, Letley DP, Limb MC, El-Omar EM, Atherton JC (2008) Toxigenic Helicobacter pylori infection precedes gastric hypochlorhydria in cancer relatives, and H. pylori virulence evolves in these families. Clin Cancer Res 14(7):2227–2235. doi:10.1158/1078-0432.CCR-07-2022
Bruce LJ (2008) Red cell membrane transport abnormalities. Curr Opin Hematol 15(3):184–190. doi:10.1097/MOH.0b013e3282f97b0a
Ernst M, Najdovska M, Grail D, Lundgren-May T, Buchert M, Tye H, Matthews VB, Armes J, Bhathal PS, Hughes NR, Marcusson EG, Karras JG, Na S, Sedgwick JD, Hertzog PJ, Jenkins BJ (2008) STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest 118(5):1727–1738
Friis-Hansen L (2006) Achlorhydria is associated with gastric microbial overgrowth and development of cancer: lessons learned from the gastrin knockout mouse. Scand J Clin Lab Invest 66(7):607–621. doi:10.1080/00365510600873894
Fu GH, Wang Y, Xi YH, Shen WW, Pan XY, Shen WZ, Jiang XS, Chen GQ (2005) Direct interaction and cooperative role of tumor suppressor p16 with band 3 (AE1). FEBS Lett 579:2105–2110. doi:10.1016/j.febslet.2005.02.063
Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, Terao S, Amagai K, Hayashi S, Asaka M (2008) Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 372(9636):392–397. doi:10.1016/S0140-6736(08)61159-9
Gawenis LR, Ledoussal C, Judd LM, Prasad V, Alper SL, Stuart-Tilley A, Woo AL, Grisham C, Sanford LP, Doetschman T, Miller ML, Shull GE (2004) Mice with a targeted disruption of the AE2 Cl−/HCO3 − exchanger are achlorhydric. J Biol Chem 279(29):30531–30539. doi:10.1074/jbc.M403779200
Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19(9):1523–1529. doi:10.1093/annonc/mdn169
Ito D, Koshino I, Arashiki N, Adachi H, Tomihari M, Tamahara S, Kurogi K, Amano T, Ono K, Inaba M (2006) Ubiquitylation-independent ER-associated degradation of an AE1 mutant associated with dominant hereditary spherocytosis in cattle. J Cell Sci 119:3602–3612. doi:10.1242/jcs.03101
Jennings ML, Gosselink PG (1995) Anion exchange protein in Southeast Asian ovalocytes: heterodimer formation between normal and variant subunits. Biochemistry 34(11):3588–3595. doi:10.1021/bi00011a013
Kopito RR (1990) Molecular biology of the anion exchanger gene family. Int Rev Cytol 123:177–199. doi:10.1016/S0074-7696(08)60674-9
Kopito RR, Lee BS, Simmons DM, Lindsey AE, Morgans CW, Schneider K (1989) Regulation of intracellular pH by a neuronal homolog of the erythrocyte anion exchanger. Cell 59(5):927–937
Kudrycki KE, Newman PR, Shull GE (1990) cDNA cloning and tissue distribution of mRNAs for two proteins that are related to the band 3 Cl−/HCO3 − exchanger. J Biol Chem 265(1):462–471
Lee CW, Rickman B, Rogers AB, Ge Z, Wang TC, Fox JG (2008) Helicobacter pylori eradication prevents progression of gastric cancer in hypergastrinemic INS-GAS mice. Cancer Res 68(9):3540–3548. doi:10.1158/0008-5472.CAN-07-6786
Louise MJ, Anastasia A, Carlos AR, Zachary S, Gary ES, Marian LM (2005) Gastric achlorhydria in H/K-ATPase-deficient (Atp4a(-/-)) mice causes severe hyperplasia, mucocystic metaplasia and upregulation of growth factors. J Gastroenterol Hepatol 20(8):1266–1278. doi:10.1111/j.1440-1746.2005.03867.x
Lynch HT, Kaurah P, Wirtzfeld D, Rubinstein WS, Weissman S, Lynch JF, Grady W, Wiyrick S, Senz J, Huntsman DG (2008) Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy. Cancer 112(12):2655–2663. doi:10.1002/cncr.23501
Meier S, Hübner CA, Groeben H, Peters J, Bingmann D, Wiemann M (2007) Expression of anion exchanger 3 influences respiratory rate in awake and isoflurane anesthetized mice. J Physiol Pharmacol 58(Suppl 5):371–378
Merchant JL (2008) What lurks beneath: IL-11, via Stat3, promotes inflammation-associated gastric tumorigenesis. J Clin Invest 118(5):1628–1631
Pang AJ, Bustos SP, Reithmeier RA (2008) Structural characterization of the cytosolic domain of kidney chloride/bicarbonate anion exchanger 1 (kAE1). Biochemistry 47(15):4510–4517. doi:10.1021/bi702149b
Poplawski T, Tomaszewska K, Galicki M, Morawiec Z, Blasiak J (2008) Promoter methylation of cancer-related genes in gastric carcinoma. Exp Oncol 30(2):112–116
Salhany JM, Cordes KA, Schopfer LM (1993) Kinetics of conformational changes associated with inhibitor binding to the purified band 3 transporter. Direct observation of allosteric subunit interactions. Biochemistry 32(29):7413–7420. doi:10.1021/bi00080a011
Shen WW, Wu J, Cai L, Liu BY, Gao Y, Chen GQ, Fu GH (2007) Expression of anion exchanger 1 sequestrates p16 in the cytoplasm in gastric and colonic adenocarcinoma. Neoplasia 9(10):812–819. doi:10.1593/neo.07403
Sipponen P (2002) Gastric cancer: pathogenesis, risks, and prevention. J Gastroenterol 37(Suppl 13):39–44. doi:10.1007/BF02990098
Stewart AK, Kurschat CE, Alper SL (2007) Role of nonconserved charged residues of the AE2 transmembrane domain in regulation of anion exchange by pH. Pflugers Arch 454(3):373–384. doi:10.1007/s00424-007-0220-8
Sugano K (2008) Gastric cancer: pathogenesis, screening, and treatment. Gastrointest Endosc Clin N Am 18(3):513–522. doi:10.1016/j.giec.2008.05.003
Tanner MJ (1997) The structure and function of band 3 (AE1): recent developments. Mol Membr Biol 14(4):155–165. doi:10.3109/09687689709048178
Vauhkonen M, Vauhkonen H, Sajantila A, Sipponen P (2005) Differences in genomic instability between intestinal- and diffuse-type gastric cancer. Gastric Cancer 8(4):238–244. doi:10.1007/s10120-005-0346-3
Vauhkonen M, Vauhkonen H, Sipponen P (2006) Pathology and molecular biology of gastric cancer. Best Pract Res Clin Gastroenterol 20(4):651–674. doi:10.1016/j.bpg.2006.03.016
Vilkin A, Levi Z, Morgenstern S, Shmuely H, Gal E, Hadad B, Hardi B, Niv Y (2008) Higher gastric mucin secretion and lower gastric acid output in first-degree relatives of gastric cancer patients. J Clin Gastroenterol 42(1):36–41
Yang Y, Wu PP, Wu J, Shen WW, Wu YL, Fu AF, Zheng L, Jin XL, Fu GH (2008) Expression of anion exchanger 2 in human gastric cancer. Exp Oncol 30(1):81–87
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W.-Q. Xu and L.-J. Song have been equally contributed to this work.
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Xu, WQ., Song, LJ., Liu, Q. et al. Expression of anion exchanger 1 is associated with tumor progress in human gastric cancer. J Cancer Res Clin Oncol 135, 1323–1330 (2009). https://doi.org/10.1007/s00432-009-0573-9
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DOI: https://doi.org/10.1007/s00432-009-0573-9