P-cadherin Overexpression Induces Partial Epithelial-to-Mesenchymal Transition and Confers Chemoresistance in Dysplastic Oral Epithelial Cells.

Chemoresistance is a major barrier to the successful treatment of oral squamous cell carcinoma. The dysplasia stage of oral tumor progression is associated with increased levels of antiapoptotic mediators as well as the cell adhesion protein placental cadherin (P-cadherin). The mechanisms by which P-cadherin may contribute to tumor progression in dysplastic oral epithelia remain unclear. In the present study, a dysplastic oral keratinocyte (DOK) cell line was utilized as a model system to investigate the effects of P-cadherin overexpression on cellular behavior and survival signaling. Compared with the controls, DOK cells that overexpressed P-cadherin displayed a mesenchymal morphology and increased levels of the chemoresistance modulator, mucin-1. P-cadherin overexpression resulted in a 2-fold decrease in apoptosis levels in response to treatment with the chemotherapeutic agent 5-fluorouracil. In the same drug-treated cells, P-cadherin overexpression increased phosphorylation of the survival kinases Akt and mitogen-activated protein kinase, as well as levels of focal adhesion kinase. The morphology changes and chemoresistance displayed by P-cadherin-overexpressing cells were consistent with an epithelial-to-mesenchymal transition. This transition may be partial, however, as P-cadherin-overexpressing cells retained expression of epithelial cadherin and exhibited a 2-fold decrease in motility. Taken together, these data suggest that during oral dysplasia, P-cadherin may continue to participate in cell-to-cell contacts while also modulating chemoresistance through the activation of survival signaling pathways.