Tumor-induced upregulation of Twist, Snail, and Slug represses the activity of the human VE-cadherin promoter

• Published in: Archives of biochemistry and biophysics 2009-02, Vol.482 (1), p.77-82
• Main Authors: Lopez, Dayami, Niu, Guilian, Huber, Philippe, Carter, W. Bradford
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Breast cancer cells; Breast Neoplasms; Cadherins - genetics; Carcinoma, Hepatocellular; Cell Line, Tumor; Culture Media, Conditioned; Endothelial cells; Endothelium, Vascular - physiology; Epithelial Cells - physiology; Female; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Liver Neoplasms; Nuclear Proteins - genetics; Plasmids; Promoter; Promoter Regions, Genetic; Repressors; RNA, Messenger - genetics; Slug; Snail; Snail Family Transcription Factors; Transcription Factors - genetics; Transcription, Genetic; Transcriptional regulation; Transfection; Twist; Twist-Related Protein 1 - genetics; VE-cadherin
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2008.11.016

Endothelial integrity is dependent on intracellular adherens junctions formed by complexes of vascular endothelial (VE)-cadherin and catenins. We have previously demonstrated that exposing endothelial cells (EC) to breast cancer cell-conditioned media (CM) for 24 h results in a reduction in VE-cadherin protein and mRNA levels. Herein, we examined the mechanism(s) involved in the downregulation of VE-cadherin by CM. Human dermal microvascular EC exposed to CM showed a downregulation in VE-cadherin promoter activity and upregulation of Twist, Slug, and Snail expression. Reporter gene analysis demonstrated a direct repression of the VE-cadherin promoter by Slug, Snail, and Twist expression plasmids. At least two E-box motifs appear to be involved in this regulatory process as shown by electrophoretic mobility shift assays. These results suggest that factors released by breast cancer cells are able to upregulate Twist, Slug, and Snail expression in EC, which in turn downregulate the activity of the VE-cadherin promoter.