Original Article

Oncogene (2006) 25, 248–259. doi:10.1038/sj.onc.1209054; published online 29 August 2005

Influence of the cytoplasmic domain of E-cadherin on endogenous N-cadherin expression in malignant melanoma

S Kuphal1 and A K Bosserhoff1

1Institute of Pathology, University of Regensburg, Regensburg, Germany

Correspondence: Dr A Bosserhoff, Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee, 11, Regensburg, Bavaria 93053, Germany. E-mail: anja.bosserhoff@klinik.uni-regensburg.de

Received 4 February 2005; Revised 5 July 2005; Accepted 27 July 2005; Published online 29 August 2005.

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Abstract

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.

Keywords:

E-cadherin, NFkappaB, N-cadherin regulation, cell contact

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