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Expression of E-cadherin transcriptional regulators in ovarian carcinoma

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Abstract

Unlike most epithelial cancers, E-cadherin expression is upregulated in ovarian carcinoma effusions compared with corresponding primary tumors. In the present study, we analyzed the anatomic site-specific expression of transcription factors that negatively regulate E-cadherin in ovarian carcinoma. Using reverse-transcription polymerase chain reaction, mRNA in situ hybridization, and Western blotting, we analyzed the expression and localization of the Snail, Slug, and SIP1 transcription factors and E-cadherin in 78 effusions, 41 primary carcinomas, and 15 solid metastases. Slug mRNA and protein expression was highest in metastases (p=0.042 and p<0.001, respectively). Snail mRNA was comparable at all anatomic sites, but higher protein expression was found in primary tumors and solid metastases compared with effusions (p<0.001). SIP1 mRNA expression was higher in effusions (p<0.001) compared to other sites. Confocal microscopy analysis of fresh and cultured cells from effusion specimens revealed cytoplasmic localization of the Snail protein in primary tumor cells, with a nuclear shift following culturing of these cells. In conclusion, E-cadherin and its negative regulators show site-dependent expression in ovarian carcinoma. In solid tumors, E-cadherin is negatively regulated by Snail and Slug. In effusions, SIP1 may be the main regulator of E-cadherin, but with a lesser level of suppression compared with primary tumors and solid metastases.

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References

  1. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia de Herreros A (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2:84–89

    Article  PubMed  CAS  Google Scholar 

  2. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A (2003) The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 116:499–511

    Article  PubMed  CAS  Google Scholar 

  3. Bukholm IK, Nesland JM, Borresen-Dale AL (2000) Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients. J Pathol 190:15–19

    Article  PubMed  CAS  Google Scholar 

  4. Cavallaro U, Christofori G (2004) Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nat Rev Cancer 4:118–132

    PubMed  CAS  Google Scholar 

  5. Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7:1267–1278

    Article  PubMed  CAS  Google Scholar 

  6. Davidson B, Goldberg I, Gotlieb WH, Kopolovic J, Ben-Baruch G, Nesland JM, Berner A, Bryne M, Reich R (1999) High levels of MMP-2, MMP-9, MT1-MMP and TIMP-2 mRNA correlate with poor survival in ovarian carcinoma. Clin Exp Metastasis 17:799–808

    Article  PubMed  CAS  Google Scholar 

  7. Davidson B, Berner A, Nesland JM, Risberg B, Berner HS, Tropé CG, Kristensen GB, Bryne M, Flørenes V-A (2000) E-cadherin and alpha-, beta-, and gamma-catenin protein expression is up-regulated in ovarian carcinoma cells in serous effusions. J Pathol 192:460–469

    Article  PubMed  CAS  Google Scholar 

  8. Davidson B, Risberg B, Reich R, Berner A (2003) Effusion cytology in ovarian cancer: new molecular methods as aids to diagnosis and prognosis. Clin Lab Med 23:729–754

    Article  PubMed  Google Scholar 

  9. Davidson B (2004) Malignant effusions: from diagnosis to biology. Diagn Cytopathol 31:246–254

    Article  PubMed  Google Scholar 

  10. Elloul S, Elstrand MB, Nesland JM, Tropé CG, Kvalheim G, Goldberg I, Reich R, Davidson B (2005) Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 103:1631–1643

    Article  PubMed  CAS  Google Scholar 

  11. Goff BA, Mandel L, Muntz HG, Melancon CH (2000) Ovarian carcinoma diagnosis. Cancer 89:2068–2075

    Article  PubMed  CAS  Google Scholar 

  12. Gotzmann J, Mikula M, Eger A, Schulte-Hermann R, Foisner R, Beug H, Mikulits W (2004) Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res 566:9–20

    Article  PubMed  CAS  Google Scholar 

  13. Hajra KM, Fearon ER (2002) Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer 34:255–268

    Article  PubMed  CAS  Google Scholar 

  14. Hajra KM, Chen DY, Fearon ER (2002) The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 62:1613–1618

    PubMed  CAS  Google Scholar 

  15. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  16. Ikenouchi J, Matsuda M, Furuse M, Tsukita S (2003) Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci 116:1959–1967

    Article  PubMed  CAS  Google Scholar 

  17. Jiao W, Miyazaki K, Kitajima Y (2002) Inverse correlation between E-cadherin and Snail expression in hepatocellular carcinoma cell lines in vitro and in vivo. Br J Cancer 86:98–101

    Article  PubMed  CAS  Google Scholar 

  18. Lambert CA, Colige AC, Munaut C, Lapiere CM, Nusgens BV (2001) Distinct pathways in the over-expression of matrix metalloproteinases in human fibroblasts by relaxation of mechanical tension. Matrix Biol 20:397–408

    Article  PubMed  CAS  Google Scholar 

  19. Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y, Miyazaki K (2004) Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer 90:1265–1273

    Article  PubMed  CAS  Google Scholar 

  20. Nieto MA (2002) The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3:155–166

    Article  PubMed  CAS  Google Scholar 

  21. Nollet F, Berx G, van Roy F (1999) The role of the E-cadherin/catenin adhesion complex in the development and progression of cancer. Molec Cell Biol Res Commun 2:77–85

    Article  CAS  Google Scholar 

  22. Oka H, Shiozaki H, Kobayashi K, Tahara H, Tamura S, Miyata M, Doki Y, Iihara K, Matsuyoshi N, Hirano S et al (1992) Immunohistochemical evaluation of E-cadherin adhesion molecule expression in human gastric cancer. Virchows Arch A Pathol Anat Histopathol 421:149–156

    Article  PubMed  CAS  Google Scholar 

  23. Pecina-Slaus N (2003) Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell Int 3:17

    Article  PubMed  Google Scholar 

  24. Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosserhoff AK (2001) Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem 276:24661–24666

    Article  PubMed  CAS  Google Scholar 

  25. Reed JA, Manahan LJ, Park CS, Brigati DJ (1992) Complete one-hour immunocytochemistry based on capillary action. Biotechniques 13:434–443

    PubMed  CAS  Google Scholar 

  26. Risinger JI, Berchuck A, Kohler MF, Boyd J (1994) Mutations of the E-cadherin gene in human gynecologic cancers. Nat Genet 7:98–102

    Article  PubMed  CAS  Google Scholar 

  27. Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Hofler H, Becker KF (2002) Differential expression of the epithelial–mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol 161:1881–1891

    PubMed  CAS  Google Scholar 

  28. Tai CT, Lin WC, Chang WC, Chiu TH, Chen GTC (2003) Classical cadherin and catenin expression in normal myometrial tissues and uterine leiomyomas. Mol Reprod Dev 64:172–178

    Article  PubMed  CAS  Google Scholar 

  29. Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    Article  PubMed  CAS  Google Scholar 

  30. Thiery JP (2003) Epithelial–mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746

    Article  PubMed  CAS  Google Scholar 

  31. Van Aken E, De Wever O, Correia da Rocha AS, Mareel M (2001) Defective E-cadherin/catenin complexes in human cancer. Virchows Arch 439:725–751

    PubMed  Google Scholar 

  32. Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R, Nagayama M (2001) Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol 37:65–71

    Article  PubMed  CAS  Google Scholar 

  33. Yokoyama K, Kamata N, Fujimoto R, Tsutsumi S, Tomonari M, Taki M, Hosokawa H, Nagayama M (2003) Increased invasion and matrix metalloproteinase-2 expression by snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol 22:891–898

    PubMed  CAS  Google Scholar 

  34. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (2004) Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial–mesenchymal transition. Nat Cell Biol 6:931–940

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 91120, Israel

    Sivan Elloul & Reuven Reich

  2. Department of Gynecologic Oncology, National Hospital–Norwegian Radium Hospital, University of Oslo, Montebello, 0310, Oslo, Norway

    Ilvars Silins & Claes G. Tropé

  3. Department of Pathology, National Hospital–Norwegian Radium Hospital, University of Oslo, Montebello, 0310, Oslo, Norway

    Ben Davidson

  4. Department of Obstetrics and Gynecology, Hadassah Medical Center, Hebrew University, Jerusalem, 91120, Israel

    Avi Benshushan

Authors
  1. Sivan Elloul
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  2. Ilvars Silins
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  3. Claes G. Tropé
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  4. Avi Benshushan
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  5. Ben Davidson
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  6. Reuven Reich
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Corresponding author

Correspondence to Ben Davidson.

Additional information

Reuven Reich is affiliated with the David R. Bloom Center for Pharmacy at the Hebrew University.

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Elloul, S., Silins, I., Tropé, C.G. et al. Expression of E-cadherin transcriptional regulators in ovarian carcinoma. Virchows Arch 449, 520–528 (2006). https://doi.org/10.1007/s00428-006-0274-6

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  • DOI: https://doi.org/10.1007/s00428-006-0274-6

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