Influence of the cytoplasmic domain of E-cadherin on endogenous N-cadherin expression in malignant melanoma.
E-cadherin is known to be an important molecule in epithelial-mesenchymal transition (EMT). Malignant transformation of melanocytes frequently attends with loss of E-cadherin expression and induction of expression of mesenchymal molecules like N-cadherin. The switch of the cadherin class is an interesting phenomenon of melanoma cells and in EMT in general. Therefore, we analysed the capacity of E-cadherin to regulate expression of N-cadherin in melanocytic cells. Our experiments revealed that melanoma cells downregulate endogenous N-cadherin expression after transient transfection of full-length E-cadherin, but also of the cytoplasmic domain of E-cadherin. Therefore, we concluded that the extracellular domain of E-cadherin and cell-cell contacts are not necessary for negative regulation of N-cadherin. Melanoma cells re-expressing full-length or cytoplasmatic E-cadherin have reduced NFkappaB activity in comparison to mock-transfected cells. Downregulation of NFkappaB activity, either directly or by re-expression of E-cadherin, led to a suppression of N-cadherin promoter activity and N-cadherin expression. Consequently, an NFkappaB-binding site in the N-cadherin promoter was characterized. In summary, our results suggest that N-cadherin is directly regulated by E-cadherin. Loss of E-cadherin induces NFkappaB activity and N-cadherin expression in tumorigenic EMT.
Kuphal
S
S
Institute of Pathology, University of Regensburg, Regensburg, Germany.
Bosserhoff
A K
AK
D001665:Binding Sites; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology*; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D014162:Transfection
D015820:Cadherins; D016328:NF-kappa B