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Tumor Biology

, Volume 35, Issue 9, pp 8645–8652 | Cite as

Loss of E-cadherin promotes migration and invasion of cholangiocarcinoma cells and serves as a potential marker of metastasis

  • Anchalee Techasen
  • Watcharin Loilome
  • Nisana Namwat
  • Narong Khuntikeo
  • Anucha Puapairoj
  • Patcharee Jearanaikoon
  • Hideyuki Saya
  • Puangrat Yongvanit
Research Article

Abstract

Tumor progression is characterized by loss of cell adhesion and increase of invasion and metastasis. E-cadherin, a cell adhesion molecule, is frequently downregulated and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT) in tumors. In this study, we investigated the expression of E-cadherin and its association with cancer invasion and prognosis in cholangiocarcinoma (CCA). Immunohistochemistry results demonstrated a statistically significant association between the positive metastasis status with low E-cadherin protein expression in human CCA tissues (P = 0.04). Statistical trends were identified for low E-cadherin level and shorter survival time (P = 0.08). Targeting the E-cadherin expression in CCA cells with siRNA caused upregulation of vimentin, a mesenchymal marker, and disappearance of the E-cadherin/β-catenin adhesion complex from cell membranes. Moreover, migration and invasion abilities of the cells were increased under this condition. These findings suggest that reduction of E-cadherin contributes to CCA progression by attenuating the strength of cellular adhesion, which affects motility as well as regulating the expression of EMT-related genes during CCA invasion and metastasis. Thus, E-cadherin can act as a central modulator of tumor cell phenotype and is a potential metastasis marker in CCA.

Keywords

E-cadherin Metastasis Cholangiocarcinoma Metastasis marker 

Notes

Acknowledgments

This work was supported by the Higher Education Research Promotion and National Research University Project of Thailand, Office of the Higher Education Commission, through the Health Cluster (SHeP-GMS), Khon Kaen University, Khon Kaen University Research Fund (grant no. 541901). The English editing of this manuscript was kindly performed by Dr. Ross H. Andrews, Faculty of Medicine, Imperial College London, UK.

Conflict of interest

None

References

  1. 1.
    Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.CrossRefPubMedGoogle Scholar
  2. 2.
    Inumaru J, Nagano O, Takahashi E, Ishimoto T, Nakamura S, Suzuki Y, et al. Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress. Gene Cell. 2009;14(6):703–16.CrossRefGoogle Scholar
  3. 3.
    Peinado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer. 2007;7(6):415–28.CrossRefPubMedGoogle Scholar
  4. 4.
    Yan S, Wang Y, Yang Q, Li X, Kong X, Zhang N, et al. Low-dose radiation-induced epithelial-mesenchymal transition through NF-kappaB in cervical cancer cells. Int J Oncol. 2013;42(5):1801–6.PubMedGoogle Scholar
  5. 5.
    Bryant DM, Stow JL. The ins and outs of E-cadherin trafficking. Trends Cell Biol. 2004;14(8):427–34.CrossRefPubMedGoogle Scholar
  6. 6.
    D’Souza-Schorey C. Disassembling adherens junctions: breaking up is hard to do. Trends Cell Biol. 2005;15(1):19–26.CrossRefPubMedGoogle Scholar
  7. 7.
    Hirohashi S. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. Am J Pathol. 1998;153(2):333–9.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Shimazui T, Schalken JA, Giroldi LA, Jansen CF, Akaza H, Koiso K, et al. Prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. Cancer Res. 1996;56(18):4154–8.PubMedGoogle Scholar
  9. 9.
    Chetty R, Serra S. Nuclear E-cadherin immunoexpression: from biology to potential applications in diagnostic pathology. Adv Anat Pathol. 2008;15(4):234–40.CrossRefPubMedGoogle Scholar
  10. 10.
    Ishii K, Shimoda M, Sugiura T, Seki K, Takahashi M, Abe M, et al. Involvement of epithelial-mesenchymal transition in adenoid cystic carcinoma metastasis. Int J Oncol. 2011;38(4):921–31.PubMedGoogle Scholar
  11. 11.
    Dorudi S, Hanby AM, Poulsom R, Northover J, Hart IR. Level of expression of E-cadherin mRNA in colorectal cancer correlates with clinical outcome. Br J Cancer. 1995;71(3):614–6.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Gagliardi G, Kandemir O, Liu D, Guida M, Benvestito S, Ruers TG, et al. Changes in E-cadherin immunoreactivity in the adenoma-carcinoma sequence of the large bowel. Virchows Arch. 1995;426(2):149–54.CrossRefPubMedGoogle Scholar
  13. 13.
    Katagiri A, Watanabe R, Tomita Y. E-cadherin expression in renal cell cancer and its significance in metastasis and survival. Br J Cancer. 1995;71(2):376–9.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Mayer B, Johnson JP, Leitl F, Jauch KW, Heiss MM, Schildberg FW, et al. E-cadherin expression in primary and metastatic gastric cancer: down-regulation correlates with cellular dedifferentiation and glandular disintegration. Cancer Res. 1993;53(7):1690–5.PubMedGoogle Scholar
  15. 15.
    Oka H, Shiozaki H, Kobayashi K, Inoue M, Tahara H, Kobayashi T, et al. Expression of E-cadherin cell adhesion molecules in human breast cancer tissues and its relationship to metastasis. Cancer Res. 1993;53(7):1696–701.PubMedGoogle Scholar
  16. 16.
    Ross JS, del Rosario AD, Figge HL, Sheehan C, Fisher HA, Bui HX. E-cadherin expression in papillary transitional cell carcinoma of the urinary bladder. Hum Pathol. 1995;26(9):940–4.CrossRefPubMedGoogle Scholar
  17. 17.
    Shimoyama Y, Hirohashi S, Hirano S, Noguchi M, Shimosato Y, Takeichi M, et al. Cadherin cell-adhesion molecules in human epithelial tissues and carcinomas. Cancer Res. 1989;49(8):2128–33.PubMedGoogle Scholar
  18. 18.
    Shiozaki H, Tahara H, Oka H, Miyata M, Kobayashi K, Tamura S, et al. Expression of immunoreactive E-cadherin adhesion molecules in human cancers. Am J Pathol. 1991;139(1):17–23.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ, et al. Cadherin switching in human prostate cancer progression. Cancer Res. 2000;60(13):3650–4.PubMedGoogle Scholar
  20. 20.
    Darai E, Scoazec JY, Walker-Combrouze F, Mlika-Cabanne N, Feldmann G, Madelenat P, et al. Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopathologic study of 60 cases. Hum Pathol. 1997;28(8):922–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Yilmaz M, Christofori G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 2009;28(1–2):15–33.CrossRefPubMedGoogle Scholar
  23. 23.
    Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest. 2009;119(6):1429–37.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Techasen A, Namwat N, Loilome W, Bungkanjana P, Khuntikeo N, Puapairoj A, et al. Tumor necrosis factor-alpha (TNF-alpha) stimulates the epithelial-mesenchymal transition regulator Snail in cholangiocarcinoma. Med Oncol. 2012;29(5):3083–91.CrossRefPubMedGoogle Scholar
  25. 25.
    Rubin MA, Mucci NR, Figurski J, Fecko A, Pienta KJ, Day ML. E-cadherin expression in prostate cancer: a broad survey using high-density tissue microarray technology. Hum Pathol. 2001;32(7):690–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Okegawa T, Pong RC, Li Y, Hsieh JT. The role of cell adhesion molecule in cancer progression and its application in cancer therapy. Acta Biochim Pol. 2004;51(2):445–57.PubMedGoogle Scholar
  27. 27.
    Cavallaro U, Christofori G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer. 2004;4(2):118–32.CrossRefPubMedGoogle Scholar
  28. 28.
    Derksen PW, Liu X, Saridin F, van der Gulden H, Zevenhoven J, Evers B, et al. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. 2006;10(5):437–49.CrossRefPubMedGoogle Scholar
  29. 29.
    Hajra KM, Fearon ER. Cadherin and catenin alterations in human cancer. Gene Chromosome Cancer. 2002;34(3):255–68.CrossRefGoogle Scholar
  30. 30.
    Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68(10):3645–54.CrossRefPubMedGoogle Scholar
  31. 31.
    Zavadil J, Haley J, Kalluri R, Muthuswamy SK, Thompson E. Epithelial-mesenchymal transition. Cancer Res. 2008;68(23):9574–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Brabletz T, Jung A, Dag S, Hlubek F, Kirchner T. beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol. 1999;155(4):1033–8.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Luo J, Lubaroff DM, Hendrix MJ. Suppression of prostate cancer invasive potential and matrix metalloproteinase activity by E-cadherin transfection. Cancer Res. 1999;59(15):3552–6.PubMedGoogle Scholar
  34. 34.
    Ara T, Deyama Y, Yoshimura Y, Higashino F, Shindoh M, Matsumoto A, et al. Membrane type 1-matrix metalloproteinase expression is regulated by E-cadherin through the suppression of mitogen-activated protein kinase cascade. Cancer Lett. 2000;157(2):115–21.CrossRefPubMedGoogle Scholar
  35. 35.
    Crawford HC, Fingleton BM, Rudolph-Owen LA, Goss KJ, Rubinfeld B, Polakis P, et al. The metalloproteinase matrilysin is a target of beta-catenin transactivation in intestinal tumors. Oncogene. 1999;18(18):2883–91.CrossRefPubMedGoogle Scholar
  36. 36.
    Gilles C, Polette M, Mestdagt M, Nawrocki-Raby B, Ruggeri P, Birembaut P, et al. Transactivation of vimentin by beta-catenin in human breast cancer cells. Cancer Res. 2003;63(10):2658–64.PubMedGoogle Scholar
  37. 37.
    Takahashi M, Tsunoda T, Seiki M, Nakamura Y, Furukawa Y. Identification of membrane-type matrix metalloproteinase-1 as a target of the beta-catenin/Tcf4 complex in human colorectal cancers. Oncogene. 2002;21(38):5861–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Hecht A, Kemler R. Curbing the nuclear activities of beta-catenin. Control over Wnt target gene expression. EMBO Rep. 2000;1(1):24–8.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Anchalee Techasen
    • 1
    • 6
  • Watcharin Loilome
    • 2
    • 6
  • Nisana Namwat
    • 2
    • 6
  • Narong Khuntikeo
    • 3
    • 6
  • Anucha Puapairoj
    • 4
    • 6
  • Patcharee Jearanaikoon
    • 1
    • 6
  • Hideyuki Saya
    • 5
  • Puangrat Yongvanit
    • 2
    • 6
  1. 1.Center for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical SciencesKhon Kaen UniversityKhon KaenThailand
  2. 2.Department of Biochemistry, Faculty of MedicineKhon Kaen UniversityKhon KaenThailand
  3. 3.Department of Surgery, Faculty of MedicineKhon Kaen UniversityKhon KaenThailand
  4. 4.Department of Pathology, Faculty of MedicineKhon Kaen UniversityKhon KaenThailand
  5. 5.Division of Gene Regulation, Institute for Advanced Medical Research, School of MedicineKeio UniversityTokyoJapan
  6. 6.Liver Fluke and Cholangiocarcinoma Research CenterKhon Kaen UniversityKhon KaenThailand

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