Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression

Nature Cell Biology volume 2, pages 76–83 (2000)Cite this article

Abstract

The Snail family of transcription factors has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial–mesenchymal transitions) during embryonic development. Epithelial–mesenchymal transitions are also determinants of the progression of carcinomas, occurring concomitantly with the cellular acquisition of migratory properties following downregulation of expression of the adhesion protein E-cadherin. Here we show that mouse Snail is a strong repressor of transcription of the E-cadherin gene. Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype and acquire tumorigenic and invasive properties. Endogenous Snail protein is present in invasive mouse and human carcinoma cell lines and tumours in which E-cadherin expression has been lost. Therefore, the same molecules are used to trigger epithelial–mesenchymal transitions during embryonic development and in tumour progression. Snail may thus be considered as a marker for malignancy, opening up new avenues for the design of specific anti-invasive drugs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Snail represses the activity of the E-cadherin promoter in epidermal cell lines.
Figure 2: Expression of E-cadherin and Snail-family members in mouse embryos.
Figure 3: Transient expression of Snail in epidermal keratinocytes induces the loss of E-cadherin and plakoglobin, loss of cell–cell adhesion and the appearance of membrane extensions.
Figure 4: Stable transfection of Snail into MDCK cells induces an epithelial–mesenchymal conversion concomitantly with the loss of epithelial markers and the gain of mesenchymal markers.
Figure 5: Snail induces a migratory and invasive phenotype in epithelial cells.
Figure 6: Endogenous Snail is present in mouse and human invasive cell lines.
Figure 7: Snail expression in mouse epidermal tumours is associated with spindle-cell carcinomas and invasive areas of squamous-cell carcinomas.
Figure 8: Endogenous Snail is expressed in human invasive tumours.

Similar content being viewed by others

References

  1. Bursdal, C. A., Damsky, C. H. & Pedersen, R. A. The role of E-cadherin and integrins in mesoderm differentiation and migration at the mammalian primitive streak. Development 118, 829–844 (1993).

    Google Scholar 

  2. Levine, E., Lee, C. H., Kintner, C. & Gumbiner, B. M. Selective disruption of E-cadherin function in early Xenopus embryos by a dominant negative mutant. Development 120, 901–909 (1994).

    CAS  PubMed  Google Scholar 

  3. Larue, L., Ohsugi, M., Hirchenhain, J. & Kemler, R. E-cadherin null mutant embryos fail to form a trophoectoderm epithelium. Proc. Natl Acad. Sci. USA 91, 8263–8267 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Riethmacher, D., Brinkmann, V. & Birchmeier, C. A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. Proc. Natl Acad. Sci. USA 92, 855–859 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gumbiner, B. M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84, 345–357 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Wheelock, M. J. & Jensen, P. J. Regulation of keratinocyte intercellular junction organization and epidermal morphogenesis by E-cadherin. J. Cell Biol. 117, 415–425 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Takeichi, M. Morphogenetic roles of classic cadherins. Curr. Opin. Cell Biol. 7, 619–627 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Huber, O., Bierkamp, C. & Kemler, R. Cadherins and catenins in development. Curr. Opin. Cell Biol. 8, 685–691 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Nieto, M. A., Sargent, M. G., Wilkinson, D. G. & Cooke, J. Control of cell behaviour during vertebrate development by Slug, a zinc finger gene. Science 264, 835–839 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Takeichi, M. Cadherins in cancer: implications for invasion and metastasis. Curr. Opin. Cell Biol. 5, 806–811 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Birchmeier, W. & Behrens, J. Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochim. Biophys. Acta 1198, 11–26 (1994).

    CAS  PubMed  Google Scholar 

  12. Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H. & Christofori, G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190–193 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Frixen, U. H. et al. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J. Cell Biol. 113, 173–185 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Vleminckx, K., Vakaet, L. J., Mareel, M., Fiers, W. & Van Roy, F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 66, 107–119 (1991).

    Article  CAS  PubMed  Google Scholar 

  15. Miyaki, M. et al. Increased cell-substratum adhesion, and decreased gelatinase secretion and cell growth, induced by E-cadherin transfection of human colon carcinoma cells. Oncogene 11, 2547–2552 (1995).

    CAS  PubMed  Google Scholar 

  16. Llorens, A. et al. Downregulation of E-cadherin in mouse skin carcinoma cells enhances a migratory and invasive phenotype linked to matrix metalloproteinase-9 gelatinase expression. Lab. Invest. 78, 1–12 (1998).

    Google Scholar 

  17. Behrens, J., Löwrick, O., Klein, H. L. & Birchmeier, W. The E-cadherin promoter: functional analysis of a GC-rich region and an epithelial cell-specific palindromic regulatory element. Proc. Natl Acad. Sci. USA 88, 11495–11499 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ringwald, M., Baribault, H., Schmidt, C. & Kemler, R. The structure of the gene coding for the mouse cell adhesion molecule uvomorulin. Nucleic Acids Res. 19, 6533–6539 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bussemakers, M. J., Giroldi, L. A., van Bokhoven, A. & Schalken, J. A. Transcriptional regulation of the human E-cadherin gene in human prostate cancer cell lines: characterization of the human E-cadherin gene promoter. Biochem. Biophys. Res. Commun. 203, 1284–1290 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Giroldi, L. A. et al. Role of E-boxes in the repression of E-cadherin expression. Biochem. Biophys. Res. Commun. 241, 453–458 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Rodrigo, I., Cato, A. C. B. & Cano, A. Regulation of E-cadherin gene expression during tumor progression: the role of a new Ets-binding site and the E-pal element. Exp. Cell Res. 248, 358–371 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Hennig, G., Löwrick, O., Birchmeier, W. & Behrens, J. Mechanisms identified in the transcriptional control of epithelial gene expression. J. Biol. Chem. 271, 595–602 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Faraldo, M. L. M., Rodrigo, I., Behrens, J., Birchmeier, W. & Cano, A. Analysis of the E-cadherin and P-cadherin promoters in murine keratinocyte cell lines from different stages of mouse skin carcinogenesis. Mol. Carcinogen. 20, 33–47 (1997).

    Article  CAS  Google Scholar 

  24. Mauhin, V., Lutz, Y., Dennefeld, C. & Alberga, A. Definition of the DNA-binding site repertoire for the Drososphila transcription factor SNAIL. Nucleic Acids Res. 21, 3951–3957 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fuse, N., Hirose, S. & Hayashi, S. Diploidy of Drosophila imaginal cells is maintained by a transcriptional repressor encoded by escargot. Genes Dev. 8, 2270–2281 (1994).

    Article  CAS  PubMed  Google Scholar 

  26. Nakayama, H., Scott, I. C. & Cross, J. C. The transition to endoreduplication in trophoblast giant cells is regulated by the mSna zinc finger transcription factor. Dev. Biol. 199, 150–163 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Nieto, M. A., Bennet, M. F., Sargent, M. G. & Wilkinson, D. G. Cloning and developmental expression of Sna, a murine homologue of the Drosophila snail gene. Development 116, 227–237 (1992).

    CAS  PubMed  Google Scholar 

  28. Smith D. E., Del Amo, F. F. & Gridley, T. Isolation of Sna, a mouse gene homologous to the Drosophila genes snail and escargot: its expression pattern suggests multiple roles during postimplantation development. Development 116, 1033–1039 (1992).

    CAS  PubMed  Google Scholar 

  29. Savagner, P., Yamada, K. M. & Thiery, J. P. The zinc finger protein Slug causes desmosome dissociation, an initial and necessary step in growth factor-induced epithelial-mesenchymal transition. J. Cell. Biol. 137, 1403–1419 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sefton, M., Sánchez, S. & Nieto M. A. Conserved and divergent roles for members of the Snail family of transcription factors in the chick and mouse embryo. Development 125, 3111–3121 (1998).

    CAS  PubMed  Google Scholar 

  31. Jiang, R., Lan, Y., Norton, C. R., Sundberg, J. P. & Gridley, T. The Slug gene is not essential for mesoderm or neural crest development in mice. Dev. Biol. 198, 277–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Navarro, P. et al. A role for the E-cadherin cell-cell adhesion molecule in tumor progression of mouse epidermal carcinogenesis. J. Cell Biol. 115, 517–533 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Isaac, A., Sargent, M. G. & Cooke, J. Control of vertebrate left-right asymmetry by a Snail-related zinc finger gene. Science 275, 1301–1304 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Lozano, E. & Cano, A. Cadherin/catenin complexes in murine epidermal keratinocytes: E-cadherin complexes containing either β-catenin or plakoglobin contribute to stable cell-cell contacts. Cell Adhes. Commun. 6, 51–67 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Gómez, M., Navarro, P. & Cano, A. Cell adhesion and tumor progression in mouse skin carcinogenesis: increased synthesis and organization of fibronectin is associated with the undifferentiated spindle phenotype. Invasion Metastasis 14, 17–26 (1994).

    PubMed  Google Scholar 

  36. Lozano, E. & Cano, A. Induction of mutual stabilization and retardation of tumor growth by coexpression of plakoglobin and E-cadherin in mouse skin spindle carcinoma cells. Mol. Carcinogen. 21, 273–287 (1998).

    Article  CAS  Google Scholar 

  37. Hay, E. D. An overview of epithelio-mesenchymal transformation. Acta Anat. 154, 8–20 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Frontelo, P. et al. Transforming growth factor β1 induces squamous carcinoma cell variants with increased metastatic abilities and a disorganized cytoskeleton. Exp. Cell Res. 244, 420–432 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Yoshiura, K. et al. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc. Natl Acad. Sci. USA 92, 7416–7419 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cano, A. et al. Expression pattern of the cell adhesion molecules E-cadherin, P-cadherin and α6β4 integrin is altered in pre-malignant skin tumors of p53-deficient mice. Int. J. Cancer 65, 254–262 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Oda, H., Tsukita, S. & Takeichi, M. Dynamic behavior of the cadherin-based cell-cell adhesion system during Drosophila gastrulation. Dev. Biol. 203, 435–450 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Ros, M., Sefton, M. & Nieto, M. A. Slug, a zinc finger gene previously implicated in the early patterning of the mesoderm and the neural crest, is also involved in chick limb development. Development 124, 1821–1829 (1997).

    CAS  PubMed  Google Scholar 

  43. Navarro, P., Lozano, E. & Cano, A. Expression of E- or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells. Possible involvement of plakoglobin. J. Cell Sci. 105, 923–934 (1993).

    CAS  PubMed  Google Scholar 

  44. Hemavathy, K., Meng, X. & Ip, Y. T. Differential regulation of gastrulation and neuroectodermal gene expression by Snail in the Drosophila embryo. Development 124, 3683–3691 (1997).

    CAS  PubMed  Google Scholar 

  45. Hay, E. D. Epithelial-mesenchymal transitions. Semin. Dev. Biol. 1, 347–356 (1990).

    Google Scholar 

  46. Duband, J. L., Monier, F., Delannet, M. & Newgreen, D. Epithelium-mesenchyme transition during neural crest development. Acta Anat. 154, 63–78 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Cook, D. M., Hinkes, M. T., Bernfield, M. & Rauscher F. J. III Transcriptional activation of the syndecan-1 promoter by the Wilms’ tumor protein WT1. Oncogene 13, 1789–1799 (1996).

    CAS  PubMed  Google Scholar 

  48. Nieto, M. A., Patel, K. & Wilkinson, D. G. In situ hybridisation analysis of chick embryos in whole mount and tissue sections. Methods Cell Biol. 51, 220–235 (1996).

    Google Scholar 

Download references

Acknowledgements

We thank G. Dhont for help with the one-hybrid screen; J.J. Arredondo for helpful advice in the design of this screen; A. Fabra for the human cell lines and tumours; M. Manzanares for help with the isolation of the human probe; M. Quintanilla for help in the tumorigenic assays; C. Bailón for assistance with confocal microscopy; C. Martinez for providing mouse embryos; A. Montes for technical assistance; M. Takeichi for the E-cadherin probe and ECCD-2 antibody; J. Behrens for E-cadherin promoter constructs; F.J. Rauscher for the pMT-CB6 vector; and M. Sefton for critical reading of the manuscript and editorial assistance. This work has been supported by the Spanish Ministry of Culture (grants DGICYT-PM95-0024 and PM98-0125 to M.A.N., SAF95-0818 and SAF98-0085-C03-01 to A.C., and PB97-0054 to F.P.), the Comunidad Autónoma de Madrid (grant 08.1/0020/97 to A.C. and M.A.N.) and the EU (grant FMRX-CT96-0065 to M.A.N).

Correspondence and requests for materials should be addressed to M.A.N. or A.C.

Author information

Author notes

  1. Isabel Rodrigo

    Present address: Institute of Mammalian Genetics, GSF Research Centre, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany

  2. Mirna A. Pérez-Moreno, Isabel Rodrigo, Annamaria Locascio, María J. Blanco, Marta G. del Barrio and M. Angela Nieto: These authors contributed equally to this work

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas (CSIC-UAM), Arturo Duperier 4, Madrid, 28029 , Spain

    Amparo Cano, Mirna A. Pérez-Moreno, Isabel Rodrigo & Francisco Portillo

  2. Instituto Cajal (CSIC), Doctor Arce 37, Madrid, 28002 , Spain

    Annamaria Locascio, María J. Blanco, Marta G. del Barrio & M. Angela Nieto

Authors
  1. Amparo Cano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mirna A. Pérez-Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabel Rodrigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Annamaria Locascio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. María J. Blanco
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marta G. del Barrio
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francisco Portillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Angela Nieto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Amparo Cano or M. Angela Nieto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cano, A., Pérez-Moreno, M., Rodrigo, I. et al. The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2, 76–83 (2000). https://doi.org/10.1038/35000025

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35000025

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing