10 Kallikrein-related peptidase 6 regulates epithelial-to-mesenchymal transition and serves as prognostic biomarker for head and neck squamous cell carcinoma patients. Issue 5 (May 2015)

• Record Type: Journal Article
• Authors: Schrader, C.; Kolb, M.; Zaoui, K.; Flechtenmacher, C.; Grabe, N.; Weber, K.-J.; Plinkert, P.K.; Heß, J.
• Is Part Of: Oral oncology. Volume 51:Issue 5(2015:May)
• Page Start: e30
• Publication Date: 2015-05
• Subjects: Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2015.02.013
• Languages: English
• ISSNs: 1368-8375

Abstract

Abstract : Introduction: The Kallikrein-related peptidase 6 (KLK6) belongs to a family of 15 secreted serine proteases with trypsin or chymotrypsin-like activity. Deregulation of KLK6 expression occurs in neurodegenerative and skin disorders, and is a common event in cancer. Most cancers were characterized by a strong increase of KLK6 transcript and protein levels as compared to normal tissues. Consequently, KLK6 represents a promising biomarker of early diagnosis and/or unfavorable prognosis in several human malignancies. However, the expression of KLK6 head and neck squamous cell carcinoma (HNSCC), and its molecular function has not been addressed so far. Materials and methods: We conducted loss-of-function and gain-of-function approaches in mucosal tumor cell lines to investigate the contribution of KLK6 in the regulation of tumor development and malignant progression. We demonstrate that silencing of KLK6 expression promotes tumor cell proliferation, migration and invasion in vitro. This phenotype is accompanied by the induction of epithelial-to-mesenchymal transition (EMT) and augments resistance against irradiation. 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. Results: KLK6 expression was detected in HNSCC cell lines (FaDu, Cal27 and SCC25), but not in HeLa cervix carcinoma cells. ShRNA-mediated silencing in FaDu cells and ectopic expression in HeLa cells unraveled an inhibitory function of extracellular functionary KLK6 on tumor cell proliferation and mobility. FaDu clones with silenced KLK6 expression displayed molecular features resembling EMT and exhibited higher resistance against irradiation. Low KLK6 protein expression in primary tumors from oropharyngeal and laryngeal SCC patients was significantly correlated with poor progression-free ( p = 0.001) and overall survival ( p < 0.0005), and served as an independent risk factor for unfavorable clinical outcome. Conclusions: This study demonstrates that low KLK6 expression serves as unfavorable risk factor for progression-free and overall survival of HNSCC patients, suggesting a context-dependent role of KLK6 in different human tumor entities. The presented data further provide experimental evidence that KLK6 is a key regulator of tumor cell proliferation, motility, and response to irradiation by modulating epithelial-to-mesenchymal transition.