Snail and Slug are major determinants of ovarian cancer invasiveness at the transcription level

Objectives. The transcriptional factors Snail and Slug have been reported to be important in cell migration during development and also during tumor metastasis. Their expression and role in ovarian cancer, hitherto unexplored, was examined to understand the molecular events in ovarian cancer metastases since the latter is responsible for the high degree of mortality associated with the disease. Methods. Ectopic expression of mSnail and mSlug in the epithelial ovarian cancer cell line SKOV3 was carried out and stable clones were selected. These were used to examine specific repression of the adherens, tight and desmosomal junction components by the two transcription factors. Furthermore, functional implications with respect to enhanced migration of cells, tumorigenecity and metastasis were also Studied. Results. The ectopic expression of Snail or Slug resulted in epithelial-mesenchymal transition (EMT), enhanced motility, invasiveness and tumorigenecity in the cell line SKOV3. In addressing the mechanisin by which Snail and Slug lead to loss of intercelhilar adhesion, specific repression of adherens junction components (E-cadherin and beta catenin), tight junction components (Occludin and ZO-1) and desmosomal junction components (Dsg2) were observed. Snail suppresses expression of adherens and tight junction components, while Slug Suppresses expression of all the three junction components; concertedly, bringing down the intercellular adhesion between cells. Further activation of these transcriptional factors in hypoxic conditions revealed a rapid upregulation of Slug expression as an immediate reaction that probably triggers off a signaling cascade leading to Snail expression. Conclusions. These results indicate distinct roles of the transcriptional factors Snail and Slug during ovarian cancer metastasis and cell Survival through mediation of EMT. (c) 2004 Elsevier Inc. All rights reserved.