Carcinogenesis Advance Access originally published online on July 14, 2009
Carcinogenesis 2009 30(10):1781-1788; doi:10.1093/carcin/bgp175
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P-cadherin induces an epithelial-like phenotype in oral squamous cell carcinoma by GSK-3beta-mediated Snail phosphorylation
Department of Oral and Maxillofacial Surgery
1 Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany
* To whom correspondence should be addressed. Tel: +49 941 943 1627; Fax: +49 941 943 1631; Email: richard.bauer{at}klinik.uni-regensburg.de
Cadherins belong to a family of Ca2+-dependent homophilic cell–cell adhesion proteins that are important for correct cellular localization and tissue integrity. They play a major role in the development and homeostasis of epithelial architecture. Recently, it has become more and more evident that P-cadherin contributes to the oncogenesis of many tumors. To analyze the role of P-cadherin in oral squamous cell carcinoma (OSCC), we used a cell line that was deficient of the classical cadherins, P-cadherin, E-cadherin and N-cadherin. This cell line was transfected with full-length P-cadherin (PCI52_PC). After overexpression of P-cadherin, PCI52_PC gained an epithelial-like brickstone morphology in contrast to the mock-transfected cells with a spindle-shaped mesenchymal morphology. Immunohistochemical analysis revealed a strong nuclear Snail staining in mock-transfected cells compared with a significantly reduced nuclear staining and translocation to the cytoplasm in P-cadherin-overexpressing cells. Interestingly, the effects triggered by P-cadherin overexpression could be reversed by transfecting the cells with an antisense P-cadherin plasmid construct. Additional investigations showed a reexpression of E-cadherin in all P-cadherin-transfected cell clones in contrast to the mock controls. Analyzing the signaling mechanism behind it, we found glycogen-synthase-kinase-3beta (GSK-3beta) bound to Snail in all cell clones. Furthermore, P-cadherin-overexpressing cell lines showed activated GSK-3beta that phosphorylated Snail leading to its cytoplasmic translocation. In summary, our results reveal P-cadherin as one major component in reconfiguring mesenchymal cells with epithelial features by triggering GSK-3beta-mediated inactivation and cytoplasmatic translocation of Snail in OSCC.
Abbreviations: EC, extracellular cadherin; EMT, epithelial to a mesenchymal transition; GSK-3beta, glycogen-synthase-kinase-3beta; MMP, matrix metalloproteinase; OSCC, oral squamous cell carcinoma; PBS, phosphate-buffered saline; PCR, polymerase chain reaction
Received April 10, 2009; revised June 7, 2009; accepted July 5, 2009.