Tumor Biology

, Volume 35, Issue 4, pp 3731–3741 | Cite as

Clinical significance of S100A2 expression in gastric cancer

  • Ying-Fu Liu
  • Qing-Qing Liu
  • Xuan Wang
  • Chun-Hua Luo
Research Article


Gastric carcinoma (GC) is one of the most common malignancies worldwide. To identify the candidate carcinoma-related biomarker in GC, comparative proteome technique was performed in resected GC tissues and matched adjacent non-cancerous gastric tissues (ANGT). As a result, S100A2 was successfully identified to be down-regulated significantly in GC compared with ANGT. Western blot analysis validated decreased expression of S100A2, and its expression level was related with the degree of tumor differentiation and status of lymph node metastasis in GC. Furthermore, immunohistochemistry analysis showed S100A2 down-expression was significantly associated with poor differentiation (P < 0.05), advanced depth of invasion (P < 0.05) and lymph node metastasis (P < 0.05) in GC. Kaplan–Meier curves showed that the relapse-free probability and the overall survival rate were significantly decreased with S100A2 expression decreasing (P < 0.05). Cox regression analysis indicated S100A2 down-expression was a negative independent prognostic biomarker for GC. A supplement of S100A2 protein by S100A2 expression vector significantly decreased the number of invaded cancer cells MGC-803. However, knockdown of S100A2 expression by siRNA interference compromised the invasion ability of MGC-803 cells. Moreover, S100A2 negatively regulated MEK/ERK signaling pathway, and activation of this signaling pathway by S100A2 down-regulation increased in vitro invasion of MGC-803 cells. In conclusion, this study demonstrated the clinical significance of S100A2 expression in GC, and loss of S100A2 expression contributes to GC development and progression. Therefore, the determination of S100A2 expression levels contributes to predict the outcome of GC patients.


S100A2 Gastric carcinoma Proteomics Prognostic factor Invasion 



This work was supported by grants from the National Natural Science Funds of China (81101764), the Fundamental Research Funds for the Central Universities (2010121104), and the Natural Science Foundation of Fujian Province of China (2011 J05099).

Conflicts of interest



  1. 1.
    Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods Mol Biol. 2009;472:467–77.PubMedCrossRefGoogle Scholar
  2. 2.
    Gomceli I, Demiriz B, Tez M. Gastric carcinogenesis. World J Gastroenterol. 2012;18(37):5164–70.PubMedCentralPubMedGoogle Scholar
  3. 3.
    Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS. Calcium-dependent and -independent interactions of the S100 protein family. Biochem J. 2006;396(2):201–14.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Heizmann CW, Fritz G, Schafer BW. S100 proteins: structure, functions and pathology. Front Biosci. 2002;7:d1356–68.PubMedCrossRefGoogle Scholar
  5. 5.
    Donato R et al. Functions of s100 proteins. Curr Mol Med. 2013;13(1):24–57.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Salama I et al. A review of the S100 proteins in cancer. Eur J Surg Oncol. 2008;34(4):357–64.PubMedCrossRefGoogle Scholar
  7. 7.
    Deshpande R et al. Biochemical characterization of S100A2 in human keratinocytes: subcellular localization, dimerization, and oxidative cross-linking. J Invest Dermatol. 2000;115(3):477–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Liu D et al. Expression of calcium-binding protein S100A2 in breast lesions. Br J Cancer. 2000;83(11):1473–9.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Almadori G et al. Diminished expression of S100A2, a putative tumour suppressor, is an independent predictive factor of neck node relapse in laryngeal squamous cell carcinoma. J Otolaryngol Head Neck Surg. 2009;38(1):16–22.PubMedGoogle Scholar
  10. 10.
    Feng G et al. Diminished expression of S100A2, a putative tumor suppressor, at early stage of human lung carcinogenesis. Cancer Res. 2001;61(21):7999–8004.PubMedGoogle Scholar
  11. 11.
    Nagy N et al. S100A2, a putative tumor suppressor gene, regulates in vitro squamous cell carcinoma migration. Lab Invest. 2001;81(4):599–612.PubMedCrossRefGoogle Scholar
  12. 12.
    Bronckart Y et al. Development and progression of malignancy in human colon tissues are correlated with expression of specific Ca(2+)-binding S100 proteins. Histol Histopathol. 2001;16(3):707–12.PubMedGoogle Scholar
  13. 13.
    Shrestha P et al. Localization of Ca(2+)-binding S100 proteins in epithelial tumours of the skin. Virchows Arch. 1998;432(1):53–9.PubMedCrossRefGoogle Scholar
  14. 14.
    El-Rifai W et al. Gastric cancers overexpress S100A calcium-binding proteins. Cancer Res. 2002;62(23):6823–6.PubMedGoogle Scholar
  15. 15.
    Bulk E et al. S100A2 induces metastasis in non-small cell lung cancer. Clin Cancer Res. 2009;15(1):22–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Ohuchida K et al. Over-expression of S100A2 in pancreatic cancer correlates with progression and poor prognosis. J Pathol. 2007;213(3):275–82.PubMedCrossRefGoogle Scholar
  17. 17.
    Smith SL et al. S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas. Br J Cancer. 2004;91(8):1515–24.PubMedCentralPubMedGoogle Scholar
  18. 18.
    Liu YF et al. Quantitative proteome analysis reveals annexin A3 as a novel biomarker in lung adenocarcinoma. J Pathol. 2009;217(1):54–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu YF et al. Identification of annexin A1 as a proinvasive and prognostic factor for lung adenocarcinoma. Clin Exp Metastasis. 2011;28(5):413–25.PubMedCrossRefGoogle Scholar
  20. 20.
    Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev. 2003;22(4):395–403.PubMedCrossRefGoogle Scholar
  21. 21.
    Welch DR et al. Transfection of constitutively active mitogen-activated protein/extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells. Cancer Res. 2000;60(6):1552–6.PubMedGoogle Scholar
  22. 22.
    Ward Y et al. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Mol Cell Biol. 2001;21(17):5958–69.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Wolf S, Haase-Kohn C, Pietzsch J. S100A2 in cancerogenesis: a friend or a foe? Amino Acids. 2011;41(4):849–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Wicki R et al. Repression of the candidate tumor suppressor gene S100A2 in breast cancer is mediated by site-specific hypermethylation. Cell Calcium. 1997;22(4):243–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Maelandsmo GM et al. Differential expression patterns of S100A2, S100A4 and S100A6 during progression of human malignant melanoma. Int J Cancer. 1997;74(4):464–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Ji J et al. Differential expression of S100 gene family in human esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2004;130(8):480–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang X et al. Down-regulation of S100A2 in lymph node metastases of head and neck cancer. Head Neck. 2007;29(3):236–43.PubMedCrossRefGoogle Scholar
  28. 28.
    Matsumoto K et al. Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. Urology. 2007;70(3):602–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Kyriazanos ID et al. Expression and prognostic significance of S100A2 protein in squamous cell carcinoma of the esophagus. Oncol Rep. 2002;9(3):503–10.PubMedGoogle Scholar
  30. 30.
    Lauriola L et al. Prognostic significance of the Ca(2+) binding protein S100A2 in laryngeal squamous-cell carcinoma. Int J Cancer. 2000;89(4):345–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Hountis P et al. Prognostic significance of different immunohistochemical S100A2 protein expression patterns in patients with operable nonsmall cell lung carcinoma. Onco Targets Ther. 2012;5:363–73.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Luo J et al. Loss of Reprimo and S100A2 expression in human gastric adenocarcinoma. Diagn Cytopathol. 2011;39(10):752–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Lapi E et al. S100A2 gene is a direct transcriptional target of p53 homologues during keratinocyte differentiation. Oncogene. 2006;25(26):3628–37.PubMedCrossRefGoogle Scholar
  34. 34.
    Mueller A et al. The calcium-binding protein S100A2 interacts with p53 and modulates its transcriptional activity. J Biol Chem. 2005;280(32):29186–93.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Ying-Fu Liu
    • 1
  • Qing-Qing Liu
    • 1
  • Xuan Wang
    • 1
  • Chun-Hua Luo
    • 2
  1. 1.Department of Basic Medical Sciences, Medical CollegeXiamen UniversityXiamenChina
  2. 2.Department of PathologyTraditional Chinese Medical Hospital of XiamenXiamenChina

Personalised recommendations