High expression of EphA3 (erythropoietin-producing hepatocellular A3) in gastric cancer is associated with metastasis and poor survival

BMC Clinical Pathology - Tập 17 - Trang 1-7 - 2017
Baongoc Nasri1, Mikito Inokuchi2, Toshiaki Ishikawa2, Hiroyuki Uetake2, Yoko Takagi3, Sho Otsuki2, Kazuyuki Kojima2, Tatsuyuki Kawano2
1Matsuzawa Hospital, Tokyo, Japan
2Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
3Department of Translational Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

Tóm tắt

As the major subfamily of receptor tyrosine, erythropoietin-producing hepatocellular (Eph) receptor has been related to progression and prognosis in different types of tumors. However, the role and mechanism of EPHA3 in gastric cancer is still not well understood. Specimen were collected from 202 patients who underwent gastric resection for gastric adenocarcinoma. The expression of EphA3 was studied using immunohistochemistry. We analyzed the clinicopathological factors and prognostic relevance of EphA3 expression in gastric cancer. High expression of EphA3 was associated with male predominance (p = 0.031), differentiated histology (p < 0.001), depth of tumor (p = 0.002), lymph node metastasis (p = 0.001), distant metastasis (p = 0.021), liver metastasis (p = 0.024), advanced stage (p < 0.001), and high HER2 expression (p = 0.017). Relapse-free survival (RFS) was significantly worse in patients with high expression of EphA3 than in those with low expression of EphA3 (p = 0.014). Multivariate analysis for RFS showed that depth of tumor [hazard ratio (HR) 9.333, 95% confidence interval (CI) 2.183–39.911, p = 0.003] and lymph node metastasis [hazard ratio (HR) 5.734, 95% confidence interval (CI) 2.349–13.997, p < 0.001] were independent prognostic factors. These findings suggest that high expression EphA3 may participate in metastasis and worse survival.

Tài liệu tham khảo

Global Cancer Statistic. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Default.aspx. American Cancer Society’s publication, Cancer Fact & Figures 2015. Gravalos C, Jimeno A. HER-2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008;19(9):1523–9. Bang YJ, Van Cutsem E, Feyereislova A, et al. ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER-2 positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010;376:687–97. Boyd AW, Bartlett PF, Lackmann M. Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov. 2014;13:39–62. Noren NK, Foos G, Hauser CA, Pasquale EB. The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl-Crk pathway. Nat Cell Biol. 2006;8:815–25. Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, et al. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell. 2009;139:679–92. Day BW, Stringer BW, Al-Ejeh F, Ting MJ, Wilson J, Ensbey KS, et al. EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme. Cancer Cell. 2013;23:238–48. Stephen LJ, Fawkes AL, Verhoeve A, Lemke G, Brown A. A critical role for the EphA3 receptor tyrosine kinase in heart development. Dev Biol. 2007;302:66–79. Keane N, Freeman C, Swords R, Giles FJ. EPHA3 as a novel therapeutic target in the hematological malignancies. Expert Rev Hematol. 2012;5:325–40. Nakagawa M, Inokuchi M, Takagi Y, Kato K, Sugita H, Otsuki S, Kojima K, Uetake H, Sugihara K. Erythropoietin-producing hepatocellular A1 is an Independent prognostic factor for gastric cancer. Ann Surg Oncol. 2015;22(7):2329–35. Miyazaki K, Inokuchi M, Takagi Y, Kato K, Kojima K, Sugihara K. EphA4 is a prognostic factor in gastric cancer. BMC Clin Pathol. 2013;13(1):19. Oates AC, Lackmann M, Power MA, Brennan C, Down LM, Do C, et al. Lu CY, Yang ZX, Zhou L, Huang ZZ, et al. High levels of EphA3 expression are associated with high invasive capacity and poor overall survival in hepatocellular carcinoma. Oncol Rep. 2013;30(5):2179–86. Zhuang G, Song W, Amato K, Hwang Y, et al. Effects of cancer-associated EPHA3 mutations on lung cancer. J Natl Cancer Inst. 2012;104(15):1182–97. Xi H-Q, Wu X-S, Wei B, Lin C. Aberrant expression of EphA3 in gastric carcinoma: correlation with tumor angiogenesis and survival. J Gastroenterol. 2012;47(7):785–94. Oates AC, Lackmann M, Power MA, Brennan C. An early developmental role for eph-ephrin interaction during vertebrate gastrulation. Mech Dev. 1999;83:77–94. Xi HQ, Zhao P. Clinicopathological significance and prognostic value of EphA3 and CD133 expression in colorectal carcinoma. J Clin Pathol. 2011;64(6):498–503. Wu R, Wang H, Wang J, et al. EphA3, induced by PC-1/PrLZ, contributes to the malignant progression of prostate cancer. Oncol Rep. 2014;32(6):2657–65. Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signaling and beyond. Nat Rev Cancer. 2010;10:165–80. Davies H, Hunter C, Smith R, et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 2005;65:7591–5. Bardelli A, Parsons DW, Silliman N, et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science. 2003;300(5621):949. Lee JS, Thorgeirsson SS. Comparative and integrative functional genomics of HCC. Oncogene. 2006;25(27):3801–9. Lai KO, Chen Y, Po HM, Lok KC, Gong K et al. Pasquale EB. Eph-ephrins bidirectional signaling in physiology and disease. Cell. 2008;133(1):38–52. Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression. J Biol Chem. 2004; 279(14):13383–92