Kallikrein-5 promotes cleavage of desmoglein-1 and loss of cell-cell cohesion in oral squamous cell carcinoma
Metadata[+] Show full item record
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] 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.
Access is limited to the campuses of the University of Missouri.