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Vol. 16, Issue 9, 4386-4397, September 2005

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Transendothelial Migration of Melanoma Cells Involves N-Cadherin-mediated Adhesion and Activation of the -Catenin Signaling Pathway

Jianfei Qi ^* , Ning Chen ^* , Junfu Wang ^* , and Chi-Hung Siu ^* 

^* Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5G 1L6, Canada

Submitted March 7, 2005; Revised June 8, 2005; Accepted June 22, 2005
Monitoring Editor: Asma Nusrat

Cancer metastasis is a multistep process involving many types of cell-cell interactions, but little is known about the adhesive interactions and signaling events during extravasation of cancer cells. Transendothelial migration of cancer cells was investigated using an in vitro assay, in which melanoma cells were seeded on top of a monolayer of endothelial cells. Attachment of melanoma cells on the endothelium induced a twofold increase in N-cadherin expression in melanoma cells and the redistribution of N-cadherin to the heterotypic contacts. Transendothelial migration was inhibited when N-cadherin expression was repressed by antisense RNA, indicating a key role played by N-cadherin. Whereas N-cadherin and -catenin colocalized in the contact regions between melanoma cells and endothelial cells during the initial stages of attachment, -catenin disappeared from the heterotypic contacts during transmigration of melanoma cells. Immunolocalization and immunoprecipitation studies indicate that N-cadherin became tyrosine-phosphorylated, resulting in the dissociation of -catenin from these contact regions. Concomitantly, an increase in the nuclear level of -catenin occurred in melanoma cells, together with a sixfold increase in -catenin-dependent transcription. Transendothelial migration was compromised in cells expressing a dominant-negative form of -catenin, thus supporting a regulatory role of -catenin signaling in this process.

Present address: Shandong Academy of Medical Sciences, Jinan 250062, Shandong Province, PR China.

Address correspondence to: Chi-Hung Siu (chi.hung.siu{at}utoronto.ca).

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