10 Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients

Abstract

Background: Dysregulated expression of Kallikrein-related peptidase 6 (KLK6) is a common feature for many human malignancies and numerous studies evaluated KLK6 as a promising biomarker for early diagnosis or unfavorable prognosis. However, the expression of KLK6 in carcinomas derived from mucosal epithelia, including head and neck squamous cell carcinoma (HNSCC), and its mode of action has not been addressed so far. Methods: Stable clones of human mucosal tumor cell lines were generated with shRNA-mediated silencing or ectopic overexpression to characterize the impact of KLK6 on tumor relevant processes in vitro. Tissue microarrays with primary HNSCC samples from a retrospective patient cohort (n = 162) were stained by immunohistochemistry and the correlation between KLK6 staining and survival was addressed by univariate Kaplan-Meier and multivariate Cox proportional hazard model analysis.

Epithelial-to-Mesenchymal Transition in the Pathogenesis and Therapy of Head and Neck Cancer

“…The loss of KLK6 in HNSCC seems to create a mesenchymal-like morphology and accelerated motility of tumor cells with an EMT-phenotype, identified by loss of E-cadherin and prominent induction of vimentin expression in HNSCC cells. The clinical relevance of these findings is supported by the fact that low KLK6 protein level in primary HNSCCs serves as an unfavorable risk factor for progression-free and overall survival [ 43 ]. Additionally, it has been shown that not only the loss of KLK6 but also the loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma [ 37 ].…”

“…In the context of HNSCC, a recent study provided experimental evidence that silencing of KLK6 activates the EMT program accompanied by a mesenchymal-like cell morphology as well as accelerated tumor cell migration and invasion [ 43 ]. In line with these findings, there is an inverse expression pattern between KLK6 and mesenchymal markers as well as key regulators of EMT in primary HNSCC of the TCGA cohort ( Figure 2 B).…”

“…In line with these findings, there is an inverse expression pattern between KLK6 and mesenchymal markers as well as key regulators of EMT in primary HNSCC of the TCGA cohort ( Figure 2 B). The clinical relevance of these findings was evident by the fact that low KLK6 protein levels in primary HNSCC serve as an unfavorable risk factor for progression-free and overall survival [ 43 ]. A critical role of KLK6 in regulating the transition between epithelial and mesenchymal phenotypes was already postulated by Pampalakis et al [ 42 ] They demonstrated that KLK6 acts as a suppressor of tumor progression by promoting MET in breast cancer cell lines, suggesting common mechanisms of KLK6 function in breast cancer and HNSCC cells.…”