title: 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.
  
  
  RESULTS
  KLK6 expression was detected in head and neck tumor cell lines (FaDu, Cal27 and SCC25), but not in HeLa cervix carcinoma cells. Silencing in FaDu cells and ectopic expression in HeLa cells unraveled an inhibitory function of KLK6 on tumor cell proliferation and mobility. FaDu clones with silenced KLK6 expression displayed molecular features resembling epithelial-to-mesenchymal transition, nuclear β-catenin accumulation and 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
  In summary, detection of low KLK6 expression in primary tumors represents a promising tool to stratify HNSCC patients with high risk for treatment failure. These patients might benefit from restoration of KLK6 expression or pharmacological targeting of signaling pathways implicated in EMT.
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany. carola.h.schrader@web.de.
authors.forename: Carola H
authors.initials: CH
authors.lastname: Schrader
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany. markus.kolb@med.uni-heidelberg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Kolb
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany. karim.zaoui@med.uni-heidelberg.de.
authors.forename: Karim
authors.initials: K
authors.lastname: Zaoui
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. christa.flechtenmacher@med.uni-heidelberg.de.
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.affiliation: Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany. niels.grabe@bioquant.uni-heidelberg.de.|Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany. niels.grabe@bioquant.uni-heidelberg.de.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany. klaus-josef.weber@med.uni-heidelberg.de.
authors.forename: Klaus-Josef
authors.initials: KJ
authors.lastname: Weber
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany. t.hielscher@Dkfz-Heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany. peter.plinkert@med.uni-heidelberg.de.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Plinkert
authors.affiliation: Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany. j.hess@dkfz.de.|Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany. j.hess@dkfz.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D048430:Cell Shape; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020868:Gene Silencing; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007610:Kallikreins / Q000378:metabolism*; D007822:Laryngeal Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D010610:Pharyngeal Neoplasms / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011379:Prognosis; D011836:Radiation Tolerance; D012307:Risk Factors; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D051176:beta Catenin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D051176:beta Catenin; C103551:KLK6 protein, human; D007610:Kallikreins