P‐cadherin Overexpression Enhances Survival Signaling in Dysplastic Oral Epithelia via the Epidermal Growth Factor Receptor

P‐cadherin is a calcium‐dependent transmembrane protein that mediates cell‐cell adhesion within oral epithelial tissue. Previous histological analyses have suggested that P‐cadherin protein levels increase in oral dysplasia and subsequently decrease in oral squamous cell carcinoma (OSCC). The epidermal growth factor receptor (EGFR) gene has also been shown to undergo amplification in the dysplastic stage of oral tumor development. In comparative studies, we found that levels of P‐cadherin were increased two‐fold in dysplastic oral keratinocytes (DOK) compared to primary human oral keratinocytes (HOK) obtained from normal oral mucosa. We hypothesized that in dysplastic oral epithelia, upregulated P‐cadherin cooperates with amplified EGFR to enhance survival signaling and facilitate tumor progression. To further explore the interaction of P‐cadherin and EGFR, DOK cells were retrovirally infected to generate stably‐selected control and P‐cadherin‐overexpressing cell lines. We have previously demonstrated that the DOK cell line exhibits comparatively high levels of EGFR expression. We found that P‐cadherin overexpression increased basal, as well as EGF‐stimulated EGFR phosphorylation levels. Furthermore, this was accompanied by increased phosphorylation of a downstream effector of EGFR, signal transducer and activator of transcription (STAT3). This increased phosphorylation was not dependent on an increase in total STAT3 protein level. STAT3 phosphorylation suggested activation of a pro‐survival mechanism, a finding that was further supported by P‐cadherin‐dependent increases in the anti‐apoptotic protein Bcl‐xL. When exposed to chemotherapeutic agents such as paclitaxel and carboplatin, P‐cadherin overexpression increased cell survival compared to control cells. P‐cadherin‐overexpressing cells treated with paclitaxel also exhibited decreased apoptosis. Further analysis confirmed that the difference in cell death was not due to altered proliferation of the two cell lines. We also explored the possibility that EGFR was activated by P‐cadherin‐mediated adherens junction formation. In contrast to ligand‐dependent signaling, we observed that calcium‐dependent cadherin engagement suppressed the phosphorylation of both EGFR and STAT3. These studies suggest that the upregulation of P‐cadherin, together with increased EGFR expression, promotes tumor progression in dysplastic oral epithelia through the activation of prosurvival signaling pathways. Support or Funding Information Midwestern University Glendale College of Osteopathic Medicine, College of Health Sciences, College of Veterinary Medicine This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .