Tumor-induced upregulation of Twist, Snail, and Slug represses the activity of the human VE-cadherin promoter.
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 24h 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.
Lopez
Dayami
D
Don and Erika Wallace Comprehensive Breast Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612-9416, USA.
Niu
Guilian
G
Huber
Philippe
P
Carter
W Bradford
WB
D015703:Antigens, CD / Q000235:genetics*; D001943:Breast Neoplasms; D015820:Cadherins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008113:Liver Neoplasms; D009687:Nuclear Proteins / Q000235:genetics*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000235:genetics*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D017077:Culture Media, Conditioned; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D000099152:Cadherin 5; C000604407:SNAI1 protein, human; C103173:TWIST1 protein, human