Clinical and Translational Oncology

, Volume 16, Issue 9, pp 783–791 | Cite as

Snail1 correlates with patient outcomes in E-cadherin-preserved gastroesophageal junction adenocarcinoma

  • H. Dong
  • L. Xie
  • C. Tang
  • S. Chen
  • Q. Liu
  • Q. Zhang
  • W. Zheng
  • Z. Zheng
  • H. Zhang
Research Article



The poor prognosis of gastroesophageal junction (GEJ) adenocarcinoma is largely associated with metastasis. We here report the first study to investigate the expression of epithelial-mesenchymal transition (EMT) markers Snail1 and E-cadherin in GEJ adenocarcinoma.


Snail1 and E-cadherin were detected by immunohistochemistry in a cohort of 128 patients with surgically resected GEJ adenocarcinoma. We assessed the pathologic and prognostic relevance in all patients and within clinically different preserved E-cadherin and reduced E-cadherin-expressing sub-groups.


Immunoreactivity for Snail1 and E-cadherin was positive in 68 and 43 % of tumors, respectively. Snail1-positive tumors had more frequent lymph node metastasis and advanced tumor stage. E-cadherin expression was highly associated with histological differentiation, tumor size, advanced stage, presence of lymph node metastasis and distant metastasis. Patients with positive E-cadherin expression or negative Snail1 expression had significantly favorable overall survival rate. In E-cadherin-preserved tumors, the expression of Snail1 was related to lymph node metastasis, advanced stage and poor patient outcome. However, Snail1 expression had no statistically significant relationship with clinicopathologic parameters or prognosis in the reduced E-cadherin-expressing sub-group. Multivariate survival analysis identified that tumor stage [hazard ratio (HR) 2.440; 95 % confidence interval (CI) 1.216–4.896; P = 0.012], lymph node metastasis (HR 2.404; 95 % CI 1.188–4.867; P = 0.015) and gender (HR 3.244; 95 % CI 1.568–6.714; P = 0.002) were independent prognostic markers for overall survival.


Snail1 may act more critically in E-cadherin-positive tumors. Evaluation of Snail1 and E-cadherin in GEJ adenocarcinoma may help in assessing malignant properties and stratifying patients.


Snail1 E-cadherin Epithelial-mesenchymal transition Gastroesophageal junction adenocarcinoma 



This work was supported in part by National Natural Science Foundation of China grants 30973508, 81071736 (H. Zhang) and 81171994 (L. Xie); Fund for University Students Innovation Program of Guangdong Province 1056010001 (W. Zheng).

Conflict of interest

No potential conflicts of interest are disclosed.

Supplementary material

12094_2013_1149_MOESM1_ESM.pdf (275 kb)
Fig. S1 GEJ adenocarcinoma tissue sections immunostained with goat IgG instead of Snail1 antibody as negative control (×400). (PDF 275 kb)
12094_2013_1149_MOESM2_ESM.pdf (165 kb)
Fig. S2 Kaplan–Meier analysis showing the overall survival of GEJ adenocarcinoma patients categorized according to the clinical stage. Statistical significance of the difference between curves of Snail1 negative-expressing and positive-expressing patients was compared in clinical stage I to II (a) and clinical stage III (b) patient subgroups. Statistical significance of the difference between curves of E-cadherin negative-expressing and positive-expressing patients was compared in clinical stage I to II (c) and clinical stage III (d) patient subgroups. (PDF 166 kb)


  1. 1.
    Moehler M, Lyros O, Gockel I, Galle PR, Lang H. Multidisciplinary management of gastric and gastroesophageal cancers. WJG. 2008;14(24):3773–80.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Menges M, Hoehler T. Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction. J Cancer Res Clin Oncol. 2009;135(1):29–38. doi: 10.1007/s00432-008-0425-z.PubMedCrossRefGoogle Scholar
  3. 3.
    Bain GH, Petty RD. Predicting response to treatment in gastroesophageal junction adenocarcinomas: combining clinical, imaging, and molecular biomarkers. Oncologist. 2010;15(3):270–84. doi: 10.1634/theoncologist.2009-0293.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Nakamura M, Iwahashi M, Nakamori M, Naka T, Ojima T, Iida T, et al. Lower mediastinal lymph node metastasis is an independent survival factor of Siewert type II and III adenocarcinomas in the gastroesophageal junction. Am Surg. 2012;78(5):567–73.PubMedGoogle Scholar
  5. 5.
    Maeda H, Okabayashi T, Nishimori I, Sugimoto T, Namikawa T, Dabanaka K, et al. Clinicopathologic features of adenocarcinoma at the gastric cardia: is it different from distal cancer of the stomach? J Am Coll Surg. 2008;206(2):306–10. doi: 10.1016/j.jamcollsurg.2007.06.306.PubMedCrossRefGoogle Scholar
  6. 6.
    Pedrazzani C, de Manzoni G, Marrelli D, Giacopuzzi S, Corso G, Minicozzi AM, et al. Lymph node involvement in advanced gastroesophageal junction adenocarcinoma. J Thorac Cardiovasc Surg. 2007;134(2):378–85. doi: 10.1016/j.jtcvs.2007.03.034.PubMedCrossRefGoogle Scholar
  7. 7.
    Lagarde SM, ten Kate FJ, de Boer DJ, Busch OR, Obertop H, van Lanschot JJ. Extracapsular lymph node involvement in node-positive patients with adenocarcinoma of the distal esophagus or gastroesophageal junction. Am J Surg Pathol. 2006;30(2):171–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Gu Y, Swisher SG, Ajani JA, Correa AM, Hofstetter WL, Liao Z, et al. The number of lymph nodes with metastasis predicts survival in patients with esophageal or esophagogastric junction adenocarcinoma who receive preoperative chemoradiation. Cancer. 2006;106(5):1017–25. doi: 10.1002/cncr.21693.PubMedCrossRefGoogle Scholar
  9. 9.
    Matsumoto M, Natsugoe S, Nakashima S, Sakamoto F, Okumura H, Sakita H, et al. Clinical significance of lymph node micrometastasis of pN0 esophageal squamous cell carcinoma. Cancer Lett. 2000;153(1–2):189–97.PubMedCrossRefGoogle Scholar
  10. 10.
    Yang Z, Zhang H, Kumar R. Regulation of E-cadherin. In: Breast Cancer Online. Cambridge University Press 2005.
  11. 11.
    Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J, et al. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 2002;21(20):3241–6. doi: 10.1038/sj.onc.1205416.PubMedCrossRefGoogle Scholar
  12. 12.
    Sobin LH, Compton CC. TNM seventh edition: what’s new, what’s changed: communication from the International Union Against Cancer and the American Joint Committee on Cancer. Cancer. 2010;116(22):5336–9. doi: 10.1002/cncr.25537.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhang H, Stephens LC, Kumar R. Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer. Clin Cancer Res. 2006;12(5):1479–86. doi: 10.1158/1078-0432.CCR-05-1519.PubMedCrossRefGoogle Scholar
  14. 14.
    Natsugoe S, Uchikado Y, Okumura H, Matsumoto M, Setoyama T, Tamotsu K, et al. Snail plays a key role in E-cadherin-preserved esophageal squamous cell carcinoma. Oncol Rep. 2007;17(3):517–23.PubMedGoogle Scholar
  15. 15.
    Uchikado Y, Okumura H, Ishigami S, Setoyama T, Matsumoto M, Owaki T, et al. Increased Slug and decreased E-cadherin expression is related to poor prognosis in patients with gastric cancer. Gastric cancer: Off J Int Gastric Cancer Assoc Jpn Gastric Cancer Assoc. 2011;14(1):41–9. doi: 10.1007/s10120-011-0004-x.CrossRefGoogle Scholar
  16. 16.
    Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002;161(5):1881–91. doi: 10.1016/S0002-9440(10)64464-1.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    He H, Chen W, Wang X, Wang C, Liu F, Shen Z, et al. Snail is an independent prognostic predictor for progression and patient survival of gastric cancer. Cancer Sci. 2012;103(7):1296–303. doi: 10.1111/j.1349-7006.2012.02295.x.PubMedCrossRefGoogle Scholar
  18. 18.
    Stanculescu D, Margaritescu C, Stepan A, Mitrut AO. E-cadherin in gastric carcinomas related to histological prognostic parameters. Rom J Morphol Embryology = Revue Roumaine de Morphologie et Embryologie. 2011;52(3 Suppl):1107–12.Google Scholar
  19. 19.
    Chan AO. E-cadherin in gastric cancer. World J Gastroenterol: WJG. 2006;12(2):199–203.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Wang ZS, Shen Y, Li X, Zhou CZ, Wen YG, Jin YB, et al. Significance and prognostic value of Gli-1 and Snail/E-cadherin expression in progressive gastric cancer. Tumour Biol: J Int Soc Oncodevelopmental Biol Med. 2013;. doi: 10.1007/s13277-013-1185-1.Google Scholar
  21. 21.
    Rosivatz E, Becker KF, Kremmer E, Schott C, Blechschmidt K, Hofler H, et al. Expression and nuclear localization of Snail, an E-cadherin repressor, in adenocarcinomas of the upper gastrointestinal tract. Virchows Arch: Int J Pathol. 2006;448(3):277–87. doi: 10.1007/s00428-005-0118-9.CrossRefGoogle Scholar
  22. 22.
    Li SL, Gao DL, Zhao ZH, Liu ZW, Zhao QM, Yu JX, et al. Correlation of matrix metalloproteinase suppressor genes RECK, VEGF, and CD105 with angiogenesis and biological behavior in esophageal squamous cell carcinoma. WJG. 2007;13(45):6076–81.PubMedCrossRefGoogle Scholar
  23. 23.
    Sung CO, Park CK, Kim SH. Classification of epithelial-mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis. Mod Pathol: Off J U. S. Can Acad Pathol, Inc. 2011;24(8):1060–8. doi: 10.1038/modpathol.2011.59.CrossRefGoogle Scholar
  24. 24.
    Barbera MJ, Puig I, Dominguez D, Julien-Grille S, Guaita-Esteruelas S, Peiro S, et al. Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene. 2004;23(44):7345–54. doi: 10.1038/sj.onc.1207990.PubMedCrossRefGoogle Scholar
  25. 25.
    Guo HM, Zhang XQ, Xu CH, Zou XP. Inhibition of invasion and metastasis of gastric cancer cells through snail targeting artificial microRNA interference. Asian Pac J Cancer Prev: APJCP. 2011;12(12):3433–8.PubMedGoogle Scholar
  26. 26.
    Castro Alves C, Rosivatz E, Schott C, Hollweck R, Becker I, Sarbia M, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol. 2007;211(5):507–15. doi: 10.1002/path.2138.PubMedCrossRefGoogle Scholar
  27. 27.
    Sawada K, Mitra AK, Radjabi AR, Bhaskar V, Kistner EO, Tretiakova M, et al. Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Res. 2008;68(7):2329–39. doi: 10.1158/0008-5472.CAN-07-5167.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Olmeda D, Jorda M, Peinado H, Fabra A, Cano A. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene. 2007;26(13):1862–74. doi: 10.1038/sj.onc.1209997.PubMedCrossRefGoogle Scholar
  29. 29.
    Roy HK, Iversen P, Hart J, Liu Y, Koetsier JL, Kim Y, et al. Down-regulation of SNAIL suppresses MIN mouse tumorigenesis: modulation of apoptosis, proliferation, and fractal dimension. Mol Cancer Ther. 2004;3(9):1159–65.PubMedGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2013

Authors and Affiliations

  • H. Dong
    • 2
  • L. Xie
    • 5
  • C. Tang
    • 7
  • S. Chen
    • 6
  • Q. Liu
    • 2
  • Q. Zhang
    • 3
  • W. Zheng
    • 4
  • Z. Zheng
    • 8
  • H. Zhang
    • 1
  1. 1.Department of Integrative Oncology, Tumor Tissue Bank, Affiliated Cancer Hospital of Shantou University Medical CollegeCancer Research Center, Shantou University Medical CollegeShantouChina
  2. 2.Cancer Research CenterShantou University Medical CollegeShantouChina
  3. 3.Department of Preventive MedicineShantou University Medical CollegeShantouChina
  4. 4.Graduate ProgramShantou University Medical CollegeShantouChina
  5. 5.Department of Radiation OncologyAffiliated Cancer Hospital of Shantou University Medical CollegeShantouChina
  6. 6.Department of Thoracic SurgeryAffiliated Cancer Hospital of Shantou University Medical CollegeShantouChina
  7. 7.Department of General SurgeryThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
  8. 8.Department of PathologyThe Second Affiliated Hospital of Shantou University Medical CollegeShantouChina

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