Abstract
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.
Highlights
Expression of Kallikreins in Normal and Malignant Oral Cells—Microarray-based profiling of aggressive Oral squamous cell carcinoma (OSCC) identified a panel of serine proteinase kallikrein-related peptidases (KLKs) (KLK-5, -7, -8, and -10) that are highly expressed in poorly differentiated murine OSCC tumors and are abundant in human OSCC [8, 27]
Numerous studies have supported a role for KLK-mediated proteolysis of desmoglein 1 (Dsg1) in the cellular desquamation process in the human stratum corneum [32,33,34,35], suggesting that KLKs may play a role in loss of cellular cohesion seen in aggressive tumors
While accumulating data support the clinical utility of various KLKs as prognostic biomarkers in these cancers, KLK expression has not been extensively evaluated in OSCC
Summary
The effect of modulating KLK5 levels on the expression and integrity of desmoglein 1 (Dsg1) was evaluated in normal oral keratinocytes and OSCC cells. Quantitative real-time PCR analysis of KLK expression ratios in normal and malignant oral cells
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have