Kallikrein-5 promotes cleavage of desmoglein-1 and loss of cell-cell cohesion in oral squamous cell carcinoma
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Oral squamous cell carcinoma (OSCC) is one of the top 10 causes of cancer deaths worldwide, with a 50% 5-year survival rate, necessitating the discovery of novel biomarkers. Using cDNA microarray analyses, we identified expression of a panel of kallikreins (KLK 5, 7, 8, and 10) associated with formation of more aggressive OSCC tumors in a murine orthotopic OSCC model. In initial studies, KLK levels in malignant OSCC cells (SCC25) were compared to cells from normal oral mucosa (OKF) using qPCR. A marked elevation of all KLKs was observed in aggressive SCC25 cells relative to OKF cells. In normal skin, KLKs 5, 7, and 8 are involved in desquamation during epidermal differentiation via proteolytic cleavage of the desmosomal cadherin component desmoglein 1 (Dsg1). As loss of cell-cell adhesion is prevalent in tumor metastasis, Dsg1 was evaluated by immunofluorescence and western blotting. SCC25 cells exhibit cleavage of Dsg1 which is blocked by treatment with a KLK inhibitor as well as by siRNA silencing of KLK5. Furthermore, cell-cell adhesion and barrier function assays demonstrate that silencing of KLK5 enforces cell-cell adhesion and improves epithelial barrier function; overexpression of KLK5 in normal oral mucosal cells (OKF) reduces cell-cell adhesion and affects epithelial barrier function. These data suggest that KLK5 may promote metastatic dissemination of OSCC by promoting loss of junctional integrity through cleavage of desmoglein 1.
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