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Molecular Biology Reports

, Volume 39, Issue 1, pp 199–208 | Cite as

S100A4 mediated cell invasion and metastasis of esophageal squamous cell carcinoma via the regulation of MMP-2 and E-cadherin activity

  • Hong-Yan Zhang
  • Xian-Zhao Zheng
  • Xin-Hua Wang
  • Xiao-Yan Xuan
  • Feng Wang
  • Shan-Shan Li
Article

Abstract

It is well documented that S100A4 is upregulated in a large amount of invasive tumors and plays a pivotal role in tumor invasion and metastasis. However, the precise role and mechanism S100A4 exerts in the invasion and metastasis of esophageal squamous cell carcinoma (ESCC) have not been fully elucidated to date. Our data demonstrated that S100A4 was overexpressed in human ESCC tissues, especially in ESCC with poor differentiation, deep invasion and lymph node metastasis. Subsequently, the knockdown of S100A4 by RNAi in ESCC cell line (EC-1) could reduce cell invasion, metastasis and proliferation ability in vitro. Most importantly, S100A4 regulated MMP-2 positively and E-cadherin negatively in vivo and in vitro to some extent. Our results suggest that S100A4 is an important factor in the invasion, metastasis and proliferation of ESCC and may control invasion and metastasis at least in part through the regulation of MMP-2 and E-cadherin activity. S100A4 may serve as a biomarker for progression of ESCC and a potential molecular target for biotherapy of ESCC.

Keywords

S100A4 Invasion Metastasis Esophageal squamous cell carcinoma 

Notes

Acknowledgments

We thank Prof. Cao (the University of Hong Kong) for providing the EC-1 cell line.

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Li Y, Sun DL, Duan YN, Zhang XJ, Wang N, Zhou RM, Chen ZF, Wang SJ (2010) Association of functional polymorphisms in MMPs genes with gastric cardia adenocarcinoma and esophageal squamous cell carcinoma in high incidence region of North China. Mol Biol Rep 37:197–205PubMedCrossRefGoogle Scholar
  3. 3.
    Mazzucchelli L (2002) Protein S100A4: too long overlooked by pathologists? Am J Pathol 160:7–13PubMedCrossRefGoogle Scholar
  4. 4.
    Liotta LA, Steeg PS, Stetler-Stevenson WG (1991) Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64:327–336PubMedCrossRefGoogle Scholar
  5. 5.
    Garrett SC, Varney KM, Weber DJ, Bresnick AR (2006) S100A4, a mediator of metastasis. J Biol Chem 281:677–680PubMedCrossRefGoogle Scholar
  6. 6.
    Ebralidze A, Tulchinsky E, Grigorian M, Afanasyeva A, Senin V, Revazova E, Lukanidin E (1989) Isolation and characterization of a gene specifically expressed in different metastatic cells and whose deduced gene product has a high degree of homology to a Ca2+-binding protein family. Genes Dev 3:1086–1093PubMedCrossRefGoogle Scholar
  7. 7.
    Goto K, Endo H, Fujiyoshi T (1988) Cloning of the sequences expressed abundantly in established cell lines: identification of a cDNA clone highly homologous to S-100, a calcium binding protein. J Biochem 103:48–53PubMedGoogle Scholar
  8. 8.
    Masiakowski P, Shooter EM (1988) Nerve growth factor induces the genes for two proteins related to a family of calcium-binding proteins in PC12 cells. Proc Natl Acad Sci USA 85:1277–1281PubMedCrossRefGoogle Scholar
  9. 9.
    Jackson-Grusby LL, Swiergiel J, Linzer DI (1987) A growth-related mRNA in cultured mouse cells encodes a placental calcium binding protein. Nucleic Acids Res 15:6677–6690PubMedCrossRefGoogle Scholar
  10. 10.
    Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG (1995) Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130:393–405PubMedCrossRefGoogle Scholar
  11. 11.
    Barraclough R, Savin J, Dube SK, Rudland PS (1987) Molecular cloning and sequence of the gene for p9Ka. A cultured myoepithelial cell protein with strong homology to S-100, a calcium-binding protein. J Mol Biol 198:13–20PubMedCrossRefGoogle Scholar
  12. 12.
    Engelkamp D, Schäfer BW, Erne P, Heizmann CW (1992) S100 alpha, CAPL, and CACY: molecular cloning and expression analysis of three calcium-binding proteins from human heart. Biochemistry 31:10258–10264PubMedCrossRefGoogle Scholar
  13. 13.
    Watanabe Y, Kobayashi R, Ishikawa T, Hidaka H (1992) Isolation and characterization of a calcium-binding protein derived from mRNA termed p9Ka, pEL-98, 18A2, or 42A by the newly synthesized vasorelaxant W-66 affinity chromatography. Arch Biochem Biophys 292:563–569PubMedCrossRefGoogle Scholar
  14. 14.
    Barraclough R (1998) Calcium-binding protein S100A4 in health and disease. Biochim Biophys Acta 1448:190–199PubMedCrossRefGoogle Scholar
  15. 15.
    Schäfer BW, Heizmann CW (1996) The S100 family of EF-hand calcium-binding proteins: functions and pathology. Trends Biochem Sci 21:134–140PubMedGoogle Scholar
  16. 16.
    Donato R (2001) S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33:637–668PubMedCrossRefGoogle Scholar
  17. 17.
    Chen XL, Zhang WG, Chen XY, Sun ZM, Liu SH (2006) Correlations of S100A4 protein expression to invasion and metastasis of non-small cell lung cancer. Ai Zheng 25:1134–1137PubMedGoogle Scholar
  18. 18.
    Matsumoto K, Irie A, Satoh T, Ishii J, Iwabuchi K, Iwamura M, Egawa S, Baba S (2007) Expression of S100A2 and S100A4 predicts for disease progression and patient survival in bladder cancer. Urology 70:602–607PubMedCrossRefGoogle Scholar
  19. 19.
    Kim JH, Kim CN, Kim SY, Lee JS, Cho D, Kim JW, Yoon SY (2009) Enhanced S100A4 protein expression is clinicopathologically significant to metastatic potential and p53 dysfunction in colorectal cancer. Oncol Rep 22:41–47PubMedGoogle Scholar
  20. 20.
    Cho YG, Nam SW, Kim TY, Kim YS, Kim CJ, Park JY, Lee JH, Kim HS, Lee JW, Park CH, Song YH, Lee SH, Yoo NJ, Lee JY, Park WS (2003) Overexpression of S100A4 is closely related to the aggressiveness of gastric cancer. APMIS 111:539–545PubMedCrossRefGoogle Scholar
  21. 21.
    Yoon CS, Hyung WJ, Lee JH, Chae YS, Won NH, Yeom BW, Choi JS (2008) Expression of S100A4, E-cadherin, alpha- and beta-catenin in gastric adenocarcinoma. Hepatogastroenterology 55:1916–1920PubMedGoogle Scholar
  22. 22.
    Zou M, Al-Baradie RS, Al-Hindi H, Farid NR, Shi Y (2005) S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma. Br J Cancer 93:1277–1284PubMedCrossRefGoogle Scholar
  23. 23.
    Moriyama-Kita M, Endo Y, Yonemura Y, Heizmann CW, Schäfer BW, Sasaki T, Yamamoto E (2004) Correlation of S100A4 expression with invasion and metastasis in oral squamous cell carcinoma. Oral Oncol 40:496–500PubMedCrossRefGoogle Scholar
  24. 24.
    Levett D, Flecknell PA, Rudland PS, Barraclough R, Neal DE, Mellon JK, Davies BR (2002) Transfection of S100A4 produces metastatic variants of an orthotopic model of bladder cancer. Am J Pathol 160:693–700PubMedCrossRefGoogle Scholar
  25. 25.
    Davies BR, Davies MP, Gibbs FE, Barraclough R, Rudland PS (1993) Induction of the metastatic phenotype by transfection of a benign rat mammary epithelial cell line with the gene for p9Ka, a rat calcium-binding protein, but not with the oncogene EJ-ras-1. Oncogene 8:999–1008PubMedGoogle Scholar
  26. 26.
    Grum-Schwensen B, Klingelhofer J, Berg CH, El-Naaman C, Grigorian M, Lukanidin E, Ambartsumian N (2005) Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res 65:3772–3780PubMedCrossRefGoogle Scholar
  27. 27.
    Mathisen B, Lindstad RI, Hansen J, El-Gewely SA, Maelandsmo GM, Hovig E, Fodstad O, Loennechen T, Winberg JO (2003) S100A4 regulates membrane induced activation of matrix metalloproteinase-2 in osteosarcoma cells. Clin Exp Metastasis 20:701–711PubMedCrossRefGoogle Scholar
  28. 28.
    Oida Y, Yamazaki H, Tobita K, Mukai M, Ohtani Y, Miyazaki N, Abe Y, Imaizumi T, Makuuchi H, Ueyama Y, Nakamura M (2006) Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer. Oncol Rep 16:457–463PubMedGoogle Scholar
  29. 29.
    Wu CY, Wu MS, Chen YJ, Chen CJ, Chen HP, Shun CT, Chen GH, Huang SP, Lin JT (2007) Clinicopathological significance of MMP-2 and TIMP-2 genotypes in gastric cancer. Eur J Cancer 43:799–808PubMedCrossRefGoogle Scholar
  30. 30.
    Takeichi M (1995) Morphogenetic roles of classic cadherins. Curr Opin Cell Biol 7:619–627PubMedCrossRefGoogle Scholar
  31. 31.
    Li S, Xi Y, Zhang H, Wang Y, Wang X, Liu H, Chen K (2010) A pivotal role for Pim-1 kinase in esophageal squamous cell carcinoma involving cell apoptosis induced by reducing Akt phosphorylation. Oncol Rep 24:997–1004PubMedGoogle Scholar
  32. 32.
    Ninomiya I, Ohta T, Fushida S, Endo Y, Hashimoto T, Yagi M, Fujimura T, Nishimura G, Tani T, Shimizu K, Yonemura Y, Heizmann CW, Schäfer BW, Sasaki T, Miwa K (2001) Increased expression of S100A4 and its prognostic significance in esophageal squamous cell carcinoma. Int J Oncol 18:715–720PubMedGoogle Scholar
  33. 33.
    Nakamura N, Takenaga K (1998) Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin Exp Metastasis 16:471–479PubMedCrossRefGoogle Scholar
  34. 34.
    Tulchinsky E, Grigorian M, Tkatch T, Georgiev G, Lukanidin E (1995) Transcriptional regulation of the mts1 gene in human lymphoma cells: the role of DNA-methylation. Biochim Biophys Acta 1261:243–248PubMedGoogle Scholar
  35. 35.
    Bjørnland K, Winberg JO, Odegaard OT, Hovig E, Loennechen T, Aasen AO, Fodstad O, Maelandsmo GM (1999) S100A4 involvement in metastasis: deregulation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in osteosarcoma cells transfected with an anti-S100A4 ribozyme. Cancer Res 59:4702–4708PubMedGoogle Scholar
  36. 36.
    Ford HL, Salim MM, Chakravarty R, Aluiddin V, Zain SB (1995) Expression of Mts1, a metastasis-associated gene, increases motility but not invasion of a nonmetastatic mouse mammary adenocarcinoma cell line. Oncogene 11:2067–2075PubMedGoogle Scholar
  37. 37.
    Zhang HY, Zheng XZ, Xuan XY, Wang XH, Wang F, Li SS (2010) Expression of S100A4 in esophageal squamous cell carcinoma and its relation to tumor invasion and metastasis. Nan Fang Yi Ke Da Xue Xue Bao 30:1541–1544PubMedGoogle Scholar
  38. 38.
    Sengupta N, MacDonald TT (2007) The role of matrix metalloproteinases in stromal/epithelial interactions in the gut. Physiology (Bethesda) 22:401–409CrossRefGoogle Scholar
  39. 39.
    Saleem M, Kweon MH, Johnson JJ, Adhami VM, Elcheva I, Khan N, Bin Hafeez B, Bhat KM, Sarfaraz S, Reagan-Shaw S, Spiegelman VS, Setaluri V, Mukhtar H (2006) S100A4 accelerates tumorigenesis and invasion of human prostate cancer through the transcriptional regulation of matrix metalloproteinase 9. Proc Natl Acad Sci USA 103:14825–14830PubMedCrossRefGoogle Scholar
  40. 40.
    Schmidt-Hansen B, Ornås D, Grigorian M, Klingelhöfer J, Tulchinsky E, Lukanidin E, Ambartsumian N (2004) Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. Oncogene 23:5487–5495PubMedCrossRefGoogle Scholar
  41. 41.
    Sherbet GV, Lakshmi MS (1998) S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. Anticancer Res 18:2415–2421PubMedGoogle Scholar
  42. 42.
    Andersen H, Mejlvang J, Mahmood S, Gromova I, Gromov P, Lukanidin E, Kriajevska M, Mellon JK, Tulchinsky E (2005) Immediate and delayed effects of E-cadherin inhibition on gene regulation and cell motility in human epidermoid carcinoma cells. Mol Cell Biol 25:9138–9150PubMedCrossRefGoogle Scholar
  43. 43.
    Yonemura Y, Endou Y, Kimura K, Fushida S, Bandou E, Taniguchi K, Kinoshita K, Ninomiya I, Sugiyama K, Heizmann CW, Schafer BW, Sasaki T (2000) Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer. Clin Cancer Res 6:4234–4242PubMedGoogle Scholar
  44. 44.
    Kimura K, Endo Y, Yonemura Y, Heizmann CW, Schafer BW, Watanabe Y, Sasaki T (2000) Clinical significance of S100A4 and E-cadherin-related adhesion molecules in non-small cell lung cancer. Int J Oncol 16:1125–1131PubMedGoogle Scholar
  45. 45.
    Keirsebilck A, Bonné S, Bruyneel E, Vermassen P, Lukanidin E, Mareel M, van Roy F (1998) E-cadherin and metastasin (mts-1/S100A4) expression levels are inversely regulated in two tumor cell families. Cancer Res 58:4587–4591PubMedGoogle Scholar
  46. 46.
    Conacci-Sorrell M, Zhurinsky J, Ben-Ze’ev A (2002) The cadherin-catenin adhesion system in signaling and cancer. J Clin Invest 109:987–991PubMedGoogle Scholar
  47. 47.
    Grigorian M, Andresen S, Tulchinsky E, Kriajevska M, Carlberg C, Kruse C, Cohn M, Ambartsumian N, Christensen A, Selivanova G, Lukanidin E (2001) Tumor suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J Biol Chem 276:22699–22708PubMedCrossRefGoogle Scholar
  48. 48.
    Parker C, Lakshmi MS, Piura B, Sherbet GV (1994) Metastasis-associated mts1 gene expression correlates with increased p53 detection in the B16 murine melanoma. DNA Cell Biol 13:343–351PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Hong-Yan Zhang
    • 1
  • Xian-Zhao Zheng
    • 2
  • Xin-Hua Wang
    • 3
  • Xiao-Yan Xuan
    • 4
  • Feng Wang
    • 1
  • Shan-Shan Li
    • 1
  1. 1.Department of PathologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouPeople’s Republic of China
  2. 2.Department of NeurologyThe People’s Hospital of Jiaozuo CityJiaozuoPeople’s Republic of China
  3. 3.Department of OncologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouPeople’s Republic of China
  4. 4.Department of Microbiology and ImmunologyCollege of Basic Medicine of Zhengzhou UniversityZhengzhouPeople’s Republic of China

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