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Molecular and Cellular Biology, October 2005, p. 9138-9150, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.9138-9150.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Immediate and Delayed Effects of E-Cadherin Inhibition on Gene Regulation and Cell Motility in Human Epidermoid Carcinoma Cells

Henriette Andersen,2,{dagger} Jakob Mejlvang,1,{dagger} Shaukat Mahmood,2 Irina Gromova,3 Pavel Gromov,3 Eugene Lukanidin,2 Marina Kriajevska,1 J. Kilian Mellon,1 and Eugene Tulchinsky1*

Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE1 9HN, United Kingdom,1 Department of Molecular Cancer Biology, Danish Cancer Society, Strandboulevarden 49, Copenhagen 2100, Denmark,2 Department of Proteomics in Cancer, Danish Cancer Society, Strandboulevarden 49, Copenhagen 2100, Denmark3

Received 1 March 2005/ Returned for modification 8 April 2005/ Accepted 21 July 2005

The invasion suppressor protein, E-cadherin, plays a central role in epithelial cell-cell adhesion. Loss of E-cadherin expression or function in various tumors of epithelial origin is associated with a more invasive phenotype. In this study, by expressing a dominant-negative mutant of E-cadherin (Ec1WVM) in A431 cells, we demonstrated that specific inhibition of E-cadherin-dependent cell-cell adhesion led to the genetic reprogramming of tumor cells. In particular, prolonged inhibition of cell-cell adhesion activated expression of vimentin and repressed cytokeratins, suggesting that the effects of Ec1WVM can be classified as epithelial-mesenchymal transition. Both short-term and prolonged expression of Ec1WVM resulted in morphological transformation and increased cell migration though to different extents. Short-term expression of Ec1WVM up-regulated two AP-1 family members, c-jun and fra-1, but was insufficient to induce complete mesenchymal transition. AP-1 activity induced by the short-term expression of Ec1WVM was required for transcriptional up-regulation of AP-1 family members and down-regulation of two other Ec1WVM-responsive genes, S100A4 and igfbp-3. Using a dominant-negative mutant of c-Jun (TAM67) and RNA interference-mediated silencing of c-Jun and Fra-1, we demonstrated that AP-1 was required for cell motility stimulated by the expression of Ec1WVM. In contrast, Ec1WVM-mediated changes in cell morphology were AP-1-independent. Our data suggest that mesenchymal transition induced by prolonged functional inhibition of E-cadherin is a slow and gradual process. At the initial step of this process, Ec1WVM triggers a positive autoregulatory mechanism that increases AP-1 activity. Activated AP-1 in turn contributes to Ec1WVM-mediated effects on gene expression and tumor cell motility. These data provide novel insight into the tumor suppressor function of E-cadherin.

* Corresponding author. Mailing address: Department of Cancer Studies and Molecular Medicine, University of Leicester, Hodgkin bldg., lab 302, Lancaster Rd., Leicester LE1 9HN, United Kingdom. Phone: 44 116 252 5584. Fax: 44 116 252 5616. E-mail: et32{at}le.ac.uk.

{dagger} H.A. and J.M. contributed equally to this work.

Molecular and Cellular Biology, October 2005, p. 9138-9150, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.9138-9150.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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