EphA4 is a prognostic factor in gastric cancer

BMC Clinical Pathology

Kenichi Sugihara²  Kazuyuki Kojima³  Keiji Kato²  Yoko Takagi¹  Mikito Inokuchi²  Kohji Miyazaki² 

[1] Department of Translational Oncology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan;Department of Surgical Oncology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan;Department of Minimally Invasive Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

关键词: Gastric cancer;    ephrinA1;    EphA2;    EphA4;   

Others  :  1084913
DOI  :  10.1186/1472-6890-13-19

 received in 2012-12-10, accepted in 2013-05-29,  发布年份 2013

【 摘 要 】

Background

Erythropoietin-producing hepatocellular (Eph) receptor, consisting of a family of receptor tyrosine kinases, plays critical roles in tumour development and is considered an attractive target for cancer therapy.

Methods

Tumour samples were obtained from 222 patients with gastric adenocarcinoma who underwent gastrectomy. The expressions of EphA2, EphA4, and ephrinA1 were evaluated immunohistochemically.

Results

High expressions of EphA2, EphA4, and ephrinA1 significantly correlated with variables related to tumour progression, including the depth of invasion, metastatic lymph nodes, pathological stage, and distant metastasis or recurrent disease. High expressions of EphA2, EphA4, and ephrinA1 were significantly associated with poorer disease-specific survival (DSS; p < 0.001, p < 0.001, p = 0.026). On multivariate analysis, EphA4 was an independent prognostic factor of DSS (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.1-4.8; p = 0.028), and EphA2 tended to be a prognostic factor (HR, 2.4; 95% CI, 1.0-5.8; p = 0.050). In stage II and III cancer, EphA4 and EphA2 were both significantly associated with shorter survival (p = 0.007 and 0.019), but only EphA2 was an independent prognostic factor (HR, 2.6; 95% CI, 1.1-6.3; p = 0.039).

Conclusion

EphA4 may play important roles in tumor progression and outcomes in patients with gastric cancer.

【 授权许可】

   
2013 Miyazaki et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010, 127:2893-2917.
• [2]Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F, Van Cutsem E: Gastric cancer. Crit Rev Oncol Hematol 2009, 71:127-164.
• [3]Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR, Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom: Capecitabine and oxaliplatin for advanced esophagogastriccancer. N Engl J Med 2008, 358:36-46.
• [4]Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M: S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008, 9:215-221.
• [5]Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK: ToGA Trial Investigators.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010, 376:687-697.
• [6]Surawska H, Ma PC, Salgia R: The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev 2004, 15:419-433.
• [7]Kullander K, Klein R: Mechanisms and functions of Eph and ephrinsignalling. Nat Rev Mol Cell Biol 2002, 3:475-486.
• [8]Pasquale EB: Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 2010, 10:165-180.
• [9]Oki M, Yamamoto H, Taniguchi H, Adachi Y, Imai K, Shinomura Y: Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. World J Gastroenterol 2008, 14:5650-5656.
• [10]Oshima T, Akaike M, Yoshihara K, Shiozawa M, Yamamoto N, Sato T, Akihito N, Nagano Y, Fujii S, Kunisaki C, Wada N, Rino Y, Tanaka K, Masuda M, Imada T: Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer. Int J Oncol 2008, 33:573-577.
• [11]World Medical Association: World Medical Association Declaration of Helsinki: Ethical Principales for Medical Research involving Human Subjects. : ; http://www.wma.net/en/30publications/10policies/b3/17c.pdf webcite
• [12]Iiizumi M, Hosokawa M, Takehara A, Chung S, Nakamura T, Katagiri T, Eguchi H, Ohigashi H, Ishikawa O, Nakamura Y, Nakagawa H: EphA4 receptor, overexpressed in pancreatic ductal adenocarcinoma, promotes cancer cell growth. Cancer Sci 2006, 97:1211-1216.
• [13]Yuan WJ, Ge J, Chen ZK, Wu SB, Shen H, Yang P, Hu B, Zhang GW, Chen ZH: Over-expression of EphA2 and EphrinA-1 in human gastric adenocarcinoma and its prognostic value for postoperative patients. Dig Dis Sci 2008, 54:2410-2417.
• [14]Nakamura R, Kataoka H, Sato N, Kanamori M, Ihara M, Igarashi H, Ravshanov S, Wang YJ, Li ZY, Shimamura T, Kobayashi T, Konno H, Shinmura K, Tanaka M, Sugimura H: EPHA2/EFNA1 expression in human gastric cancer. Cancer Sci 2005, 96:42-47.
• [15]Brantley-Sieders DM, Jiang A, Sarma K, Badu-Nkansah A, Walter DL, Shyr Y, Chen J: Eph/ephrin profiling in human breast cancer reveals significant associations between expression level and clinical outcome. PLoS One 2011, 6:e24426.
• [16]Wang B: Cancer cells exploit the Eph-ephrin system to promote invasion and metastasis: tales of unwitting partners. Sci Signal 2011, 4:pe28.
• [17]Fukai J, Yokote H, Yamanaka R, Arao T, Nishio K, Itakura T: EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line. Mol Cancer Ther 2008, 7:2768-2778.
• [18]Sugimura H, Wang JD, Mori H, Tsuboi M, Nagura K, Igarashi H, Tao H, Nakamura R, Natsume H, Kahyo T, Shinmura K, Konno H, Hamaya Y, Kanaoka S, Kataoka H, Zhou XJ: EPH-EPHRIN in human gastrointestinal cancers. World J Gastrointest Oncol 2010, 2:421-428.
• [19]Noberini R, Koolpe M, Peddibhotla S, Dahl R, Su Y, Cosford ND, Roth GP, Pasquale EB: Small molecules can selectively inhibit ephrin binding to the EphA4 and EphA2 receptors. J Biol Chem 2008, 283:29461-29472.
• [20]Takeuchi S, Yamaki N, Iwasato T, Negishi M, Katoh H: Beta2-chimaerin binds to EphA receptors and regulates cell migration. FEBS Lett 2009, 583:1237-1242.
• [21]Kinch MS, Carles-Kinch K: Overexpression and functional alterations of the EphA2 tyrosine kinase in cancer. Clin Exp Metastasis 2003, 20:59-68.
• [22]Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS: EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 2001, 61:2301-2306.
• [23]Kinch MS, Moore MB, Harpole DH Jr: Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res 2003, 9:613-618.
• [24]Zeng G, Hu Z, Kinch MS, Pan CX, Flockhart DA, Kao C, Gardner TA, Zhang S, Li L, Baldridge LA, Koch MO, Ulbright TM, Eble JN, Cheng L: High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am J Pathol 2003, 163:2271-2276.
• [25]Abraham S, Knapp DW, Cheng L, Snyder PW, Mittal SK, Bangari DS, Kinch M, Wu L, Dhariwal J, Mohammed SI: Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder. Clin Cancer Res 2006, 12:353-360.
• [26]Thaker PH, Deavers M, Celestino J, Thornton A, Fletcher MS, Landen CN, Kinch MS, Kiener PA, Sood AK: EphA2 expression is associated with aggressive features in ovarian carcinoma. Clin Cancer Res 2004, 10:5145-5150.
• [27]Xu F, Zhong W, Li J, Shanshen Z, Cui J, Nesland JM, Suo Z: Predictive value of EphA2 and EphrinA-1 expression in oesophageal squamous cell carcinoma. Anticancer Res 2005, 25:2943-2950.
• [28]Mudali SV, Fu B, Lakkur SS, Luo M, Embuscado EE, Iacobuzio-Donahue CA: Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status. Clin Exp Metastasis 2006, 23:357-365.
• [29]Kataoka H, Igarashi H, Kanamori M, Ihara M, Wang JD, Wang YJ, Li ZY, Shimamura T, Kobayashi T, Maruyama K, Nakamura T, Arai H, Kajimura M, Hanai H, Tanaka M, Sugimura H: Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer. Cancer Sci 2004, 95:136-141.
• [30]Wu D, Suo Z, Kristensen GB, Li S, Troen G, Holm R, Nesland JM: Prognostic value of EphA2 and EphrinA-1 in squamous cell cervical carcinoma. Gynecol Oncol 2004, 94:312-319.
• [31]Han L, Dong Z, Qiao Y, Kristensen GB, Holm R, Nesland JM, Suo Z: The clinical significance of EphA2 and Ephrin A-1 in epithelial ovarian carcinomas. Gynecol Oncol 2005, 99:278-286.
• [32]Wang YJ, Ota S, Kataoka H, Kanamori M, Li Z, Band H, Tanaka M, Sugimura H: Negative regulation of EphA2 receptor by Cbl. Biochem Biophys Res Commun 2002, 296:214-20.
• [33]Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL, Pasquale EB: The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 2000, 19:6043-6052.
• [34]Duxbury MS, Ito H, Zinner MJ, Ashley SW, Whang EE: EphA2: a determinant of malignant cellular behavior and a potential therapeutic target in pancreatic adenocarcinoma. Oncogene 2004, 23:1448-1456.