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Genetic Profiling of Epithelial Cells Expressing E-Cadherin Repressors Reveals a Distinct Role for Snail, Slug, and E47 Factors in Epithelial-Mesenchymal Transition

¹ Breast and Gynecological Cancer Group, Centro Nacional de Investigaciones Oncológicas; ² Departamento de Bioquímica, UAM, Instituto de Investigaciones Biomédicas "Alberto Sols," CSIC-UAM, Madrid, Spain; and ³ Institut d'Investigació Bellvitge, IDIBELL, Barcelona, Spain

Requests for reprints: Amparo Cano, Instituto de Investigaciones Biomedicas, CSIC-UAM, Arturo Duperier, 4. 28029 Madrid, Spain. Phone: 34-91-5854411; E-mail: acano{at}iib.uam.es. Jose Palacios, Servicio de Anatomia Patologica, Hospital Virgen del Rocio, Avenida Manuel Siurot, 43013 Sevilla, Spain. Phone: 34-95-5013029; E-mail: jose.palacios.sspa{at}juntadeandalucia.es.

The transcription factors Snail, Slug, and bHLH E47 have been recently described as direct repressors of E-cadherin and inducers of epithelial-mesenchymal transition (EMT) and invasion when overexpressed in epithelial cells. Although a role of those factors in tumor progression and invasion has been proposed, whether the different repressors play distinct or redundant roles in the tumorigenic process has not been established. To further investigate this important issue, we have analyzed the gene expression profiling of Madin-Darby canine kidney (MDCK) epithelial cells expressing the different repressors (MDCK-Snail, MDCK-Slug, and MDCK-E47 cells) versus control MDCK cells by cDNA microarrays. A total of 243 clones (228 genes and 15 expressed sequence tags) were found to be differentially expressed between either of the three MDCK-derived cell lines and control MDCK cells. Twenty two of the candidate genes were validated by Northern blot, Western blot, immunofluorescence, and promoter analyses in cell lines and by immunohistochemistry in xenografted tumors. Gene clustering analysis indicated that about a third of the 243 candidate genes were common to MDCK cells expressing Snail, Slug, or E47 factors, whereas the rest of the genes were regulated in only one or two cell types. Differentially regulated genes include those related to EMT (45 genes), transcriptional regulation (18 genes), cell proliferation and signaling (54 genes), apoptosis (12 genes), and angiogenesis (9 genes). These results indicate that Snail, Slug, and E47 transcription factors induce common and specific genetic programs, supporting a differential role of the factors in tumor progression and invasion. (Cancer Res 2006; 66(19): 9543-56)

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