Kallikrein-5 Promotes Cleavage of Desmoglein-1 and Loss of Cell-Cell Cohesion in Oral Squamous Cell Carcinoma

• Published in: The Journal of biological chemistry Vol. 286; no. 11; pp. 9127 - 9135
• Main Authors: Jiang, Rong, Shi, Zonggao, Johnson, Jeffrey J., Liu, Yueying, Stack, M. Sharon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.03.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Adhesion; Animals; Cancer Therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Adhesion; Cell Adhesion - genetics; Cell Aggregation; Cell Biology; Cell Dissociation; Cell Junctions; Cell Line, Transformed; Cell Line, Tumor; Desmoglein 1 - genetics; Desmoglein 1 - metabolism; Desmoglein-1; Desmosome; Gene Silencing; Humans; Kallikrein; Kallikreins - genetics; Kallikreins - metabolism; Mice; Neoplasm Metastasis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oral Cancer; Tongue Neoplasms - genetics; Tongue Neoplasms - metabolism; Tongue Neoplasms - pathology; Cancer Therapy; Cell Dissociation; Kallikrein; Cell Aggregation; Oral Cancer; Cell Junctions; Desmosome; Adhesion; Cell Adhesion; Desmoglein-1
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.191361

Oral squamous cell carcinoma (OSCC) ranks among the top 8 causes of cancer death worldwide, with only a 60% 5-year survival rate, highlighting the need for discovery of novel biomarkers and therapeutic targets. We have previously reported that expression of a panel of serine proteinase kallikreins (KLK 5, 7, 8, and 10) is correlated with formation of more aggressive OSCC tumors in a murine orthotopic OSCC model and is elevated in human OSCC. Current studies focus on understanding the potential role of KLK5 in OSCC progression. In initial studies, KLK levels in malignant OSCC cells (SCC25) were compared with cells from normal oral mucosa (OKF/6) and pre-malignant oral keratinocytes (pp126) using qPCR. A marked elevation of all KLKs was observed in aggressive SCC25 cells relative to OKF/6 cells. In normal skin, KLKs are involved in desquamation during epidermal differentiation via proteolytic cleavage of the desmosomal cadherin component desmoglein 1 (Dsg1). As loss of cell-cell cohesion is prevalent in tumor metastasis, Dsg1 integrity was evaluated. Results show that SCC25 cells exhibit cleavage of Dsg1, which is blocked by proteinase inhibitor treatment as well as by siRNA silencing of KLK5 expression. Furthermore, cell-cell aggregation assays demonstrate that silencing of KLK5 enforces cell-cell adhesion; conversely, overexpression of KLK5 in normal oral mucosal cells (OKF/6) enhances cell dispersal. These data suggest that KLK5 may promote metastatic dissemination of OSCC by promoting loss of junctional integrity through cleavage of desmoglein 1.