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Digestive Diseases and Sciences

, Volume 57, Issue 5, pp 1253–1260 | Cite as

ZEB2 Promotes the Metastasis of Gastric Cancer and Modulates Epithelial Mesenchymal Transition of Gastric Cancer Cells

  • Ying-Huan Dai
  • Ya-Ping Tang
  • Hong-Yi Zhu
  • Liang Lv
  • Yi Chu
  • Yu-Qian Zhou
  • Ji-Rong HuoEmail author
Original Article

Abstract

Background

Invasion and metastasis are the hallmarks of advanced gastric cancer progression. Therefore, it is urgent to overcome metastasis in order to improve the survival of gastric cancer patients.

Aims

This study aimed to examine the expression of ZEB2 in gastric cancer samples and analyze its correlation with clinicopathologic features. In addition, the molecular mechanism by which ZEB2 contributes to gastric cancer metastasis will be explored.

Methods

ZEB2 expression in clinical gastric cancer samples was evaluated by immunohistochemical analysis. ZEB2 was knocked-down in HGC27 gastric cancer cells by shRNA and the effects on cell invasion and migration were examined by in vitro cell invasion and migration assays. The expression of epithelial marker E-cadherin, mesenchymal markers fibronecin and vimentin, and MMPs was detected by western blot analysis.

Results

The expression of ZEB2 was positively correlated with the depth of invasion, lymph node metastasis and TNM stage. In addition, patients with positive ZEB2 expression showed a significantly shorter overall survival time than did patients with negative ZEB2. shRNA mediated knockdown of ZEB2 resulted in reduced invasion and migration of HGC27 cells, along with the upregulation of E-cadherin and downregulation of fibronecin, vimentin, MMP2, and MMP9.

Conclusions

ZEB2 expression is closely associated with the clinicopathological parameters of gastric cancer. ZEB2 promotes gastric cancer cell migration and invasion at least partly via the regulation of epithelial-mesenchymal transition. ZEB2 is a potential target for gene therapy of aggressive gastric cancer.

Keywords

ZEB2 Gastric cancer Migration Invasion Epithelial-mesenchymal transition 

Notes

Acknowledgments

The research was supported by the Project of Science and Technology Bureau of Hunan Province, China (2011FJ6025).

Conflict of interest

None.

References

  1. 1.
    Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F, Van Cutsem E. Gastric cancer. Crit Rev Oncol Hematol. 2005;54:209–241.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454.PubMedCrossRefGoogle Scholar
  4. 4.
    Cardiff RD. Epithelial to mesenchymal transition tumors: fallacious or snail’s pace? Clin Cancer Res. 2005;11:8534–8553.PubMedCrossRefGoogle Scholar
  5. 5.
    Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res. 2005;65:5991–5995.PubMedCrossRefGoogle Scholar
  6. 6.
    Batlle E, Sancho E, Franci C, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000;2:84–89.PubMedCrossRefGoogle Scholar
  7. 7.
    Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 2002;62:1613–1618.PubMedGoogle Scholar
  9. 9.
    Vernon AE, LaBonne C. Tumor metastasis: a new twist on epithelial-mesenchymal transitions. Curr Biol. 2004;14:R719–R721.PubMedCrossRefGoogle Scholar
  10. 10.
    Perez-Moreno MA, Locascio A, Rodrigo I, et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem. 2001;276:27424–27431.PubMedCrossRefGoogle Scholar
  11. 11.
    Comijn J, Berx G, Vermassen P, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell. 2001;7:1267–1278.PubMedCrossRefGoogle Scholar
  12. 12.
    Eger A, Aigner K, Sonderegger S, et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005;24:2375–2385.PubMedCrossRefGoogle Scholar
  13. 13.
    Van de Putte T, Maruhashi M, Francis A, et al. Mice lacking Zfhx1b, the gene that codes for Smad-interacting protein-1, reveal a role for multiple neural crest cell defects in the etiology of Hirschsprung disease-mental retardation syndrome. Am J Hum Genet. 2003;72:465–470.PubMedCrossRefGoogle Scholar
  14. 14.
    Vandewalle C, Comijn J, De Craene B, et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell–cell junctions. Nucleic Acids Res. 2005;33:6566–6578.PubMedCrossRefGoogle Scholar
  15. 15.
    Sayan AE, Griffiths TR, Pal R, et al. SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proc Natl Acad Sci USA. 2009;106:14884–14889.PubMedCrossRefGoogle Scholar
  16. 16.
    Rosivatz E, Becker I, Specht K, et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002;161:1881–1891.PubMedCrossRefGoogle Scholar
  17. 17.
    Ohta H, Aoyagi K, Fukaya M, et al. Cross talk between hedgehog and epithelial–mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers. Br J Cancer. 2009;100:389–398.PubMedCrossRefGoogle Scholar
  18. 18.
    Elloul S, Elstrand MB, Nesland JM, et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer. 2005;103:1631–1643.PubMedCrossRefGoogle Scholar
  19. 19.
    Yoshihara K, Tajima A, Komata D, et al. Gene expression profiling of advanced-stage serous ovarian cancers distinguishes novel subclasses and implicates ZEB2 in tumor progression and prognosis. Cancer Sci. 2009;100:1421–1428.PubMedCrossRefGoogle Scholar
  20. 20.
    Imamichi Y, Konig A, Gress T, Menke A. Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer. Oncogene. 2007;26:2381–2385.PubMedCrossRefGoogle Scholar
  21. 21.
    Maeda G, Chiba T, Okazaki M, et al. Expression of SIP1 in oral squamous cell carcinomas: implications for E-cadherin expression and tumor progression. Int J Oncol. 2005;27:1535–1541.PubMedGoogle Scholar
  22. 22.
    Sobin LH, Gospodarowicz MK, Wittekind C. UICC TNM classification of malignant tumours. 7th ed. New York: Wiley-Blackwell; 2009.Google Scholar
  23. 23.
    Li YZ, Zhao P, Han WD. Clinicopathological significance of LRP16 protein in 336 gastric carcinoma patients. World J Gastroenterol. 2009;15:4833–4837.PubMedCrossRefGoogle Scholar
  24. 24.
    Verschueren K, Remacle JE, Collart C, et al. SIP1, a novel zinc finger/homeodomain repressor, interacts with smad proteins and binds to 5′-CACCT sequences in candidate target genes. J Biol Chem. 1999;274:20489–20498.PubMedCrossRefGoogle Scholar
  25. 25.
    Cowin P, Rowlands TM, Hatsell SJ. Cadherins and catenins in breast cancer. Curr Opin Cell Biol. 2005;17:499–508.PubMedCrossRefGoogle Scholar
  26. 26.
    Hajra KM, Fearon ER. Cadherin and catenin alterations in human cancer. Genes Chromosom Cancer. 2002;34:255–268.PubMedCrossRefGoogle Scholar
  27. 27.
    Rashid MG, Sanda MG, Vallorosi CJ, Rios-Doria J, Rubin MA, Day ML. Posttranslational truncation and inactivation of human E-cadherin distinguishes prostate cancer from matched normal prostate. Cancer Res. 2001;61:489–492.PubMedGoogle Scholar
  28. 28.
    Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402–405.PubMedCrossRefGoogle Scholar
  29. 29.
    Van Aken E, De Wever O, Correia da Rocha AS, Mareel M. Defective E-cadherin/catenin complexes in human cancer. Virchows Arch. 2001;439:725–751.PubMedGoogle Scholar
  30. 30.
    Bindels S, Mestdagt M, Vanderwalle C, et al. Regulation of vimentin by Sip1 in human epithelial breast tumor cells. Oncogene. 2006;25:4975–4985.PubMedCrossRefGoogle Scholar
  31. 31.
    Miyoshi A, Kitajima Y, Sumi K, et al. Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer. 2004;90:1265–1273.PubMedCrossRefGoogle Scholar
  32. 32.
    Xia M, Hu M, Wang J, et al. Identification of the role of Smad interacting protein 1 (SIP1) in glioma. J Neurooncol. 2010;97:225–232.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ying-Huan Dai
    • 1
  • Ya-Ping Tang
    • 1
  • Hong-Yi Zhu
    • 1
  • Liang Lv
    • 1
  • Yi Chu
    • 1
  • Yu-Qian Zhou
    • 1
  • Ji-Rong Huo
    • 1
    Email author
  1. 1.Department of GastroenterologySecond Xiangya Hospital of Central South UniversityChangshaChina

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