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

Schrader, C.; Kolb, M; Zaoui, Karim; Flechtenmacher, Christa; Grabe, Niels; Weber, Klaus-Josef; Hielscher, Thomas; Plinkert, Peter K.; Heß, Jochen

doi:10.1186/s12943-015-0381-6

Cited by 46 publications

(50 citation statements)

References 55 publications

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“…These data are supported by recent findings in head and neck cancer squamous cell carcinoma and question the general oncogenic role of KLK6 and emphasize the importance to consider its context-dependent regulation and function [21,22,31].…”

Section: Discussionsupporting

confidence: 82%

“…However, Pampalakis et al provided compelling evidence that KLK6 could also act as suppressor of malignant progression by promoting mesenchymal-to-epithelial transition [22]. These data are supported by recent findings in head and neck cancer squamous cell carcinoma and question the general oncogenic role of KLK6 and emphasize the importance to consider its context-dependent regulation and function [21,22,31].…”

Section: Discussionmentioning

confidence: 84%

“…Because of the aggressive and destructive growth pattern of this tumor entity, more efficient systemic therapies, and prognostic markers are urgently needed. Aberrant expression of KLK6 has been detected in a variety of malignant tumors like pancreas, breast [31], ovarian, skin cancer [32], HNSCC [22] and glioma [20]. An increase in KLK6 expression is a common feature of most human malignancies, but the correlation between KLK6 upregulation and the clinical outcome is poorly understood and even led to controversial findings concerning tumor-regulating properties of KLK6 in tumor [21,31,32].…”

Section: Discussionmentioning

confidence: 99%

“…In HNSCC and breast cancer cells, reactivation of KLK6 was not correlated with poor clinical outcome, but associated with prominent down-regulation of Vimentin, a protein that is expressed in mesenchymal cells. These data suggest a common inhibitory function of KLK6 on Vimentin expression in breast and mucosal epithelial cells [22]; however, the molecular mechanism remains to be fully elucidated. Since the role of KLK6 has not been described in MMHN, the major objective of this study was to analyze KLK6 expression in MMHN and to further detect a possible correlation with the clinical outcome.…”

Section: Introductionmentioning

confidence: 98%

“…In several publications, KLK6 has also been described as a promising biomarker for early diagnosis and clinical outcome [20]. However, recent studies questioned the general oncogenic role of KLK6 and stressed the importance to consider its context-dependent, tumor-protective function, as exemplified in breast and renal cancer as well as squamous cell carcinoma of the head and neck (HNSCC) [21,22]. Although KLK6 has been related to neoplastic transformation and malignant progression, the regulation and function of KLK6 under physiological and pathological settings is poorly understood, and is most likely influenced by multiple mechanisms, including gene copy number imbalances [17], exposure to steroid hormones [15,23], epigenetic events such as gene promoter hyper-methylation, oncogenic signaling [24,25] and posttranscriptional control by miRNAs [17,26,27].…”

Section: Introductionmentioning

confidence: 99%

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Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

Thierauf

Veit

Lennerz

et al. 2016

Head and Neck Pathol

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Mucosal melanomas of the head and neck (MMHN) are aggressive tumors with poor prognosis, different opposed to cutaneous melanoma. In this study, we characterized primary mucosal malignant melanoma for the expression of Kallikrein-related peptidase 6 (KLK6), a member of the KLK family with relevance to the malignant phenotype in various cancer types including cutaneous melanoma. Paraffin-embedded MMHN of 22 patients were stained immunohistochemically for KLK6 and results were correlated with clinical and pathological data. In 77.3% (17/22) of MMHN cases, positive KLK6 staining was found. Staining pattern for tumor cells showed a predominant cytoplasmic staining. However, in six cases we also observed a prominent nuclear staining. MMHN with a high KLK6 expression showed significantly better outcome concerning local recurrence-free survival (p = 0.013) and nuclear KLK6 staining was significantly associated with the survival status (p = 0.027). Overexpression of KLK6 was detected in more than 70% of MMHN and approximately 40% of tumors showed a strong expression pattern. Correlation between clinical outcome of MMHN patients and overexpression of KLK6 has not been addressed so far. Our data demonstrate for the first time increased levels of KLK6 in MMHN and strengthen the hypothesis that there might be a context-specific regulation and function of KLK6 in mucosal melanoma.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

Thierauf

Veit

Lennerz

et al. 2016

Head and Neck Pathol

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Biochemical pathways mediated by KLK6 protease in breast cancer

et al. 2019

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Kallikrein‐related peptidase 6 (KLK6) is a serine protease normally expressed in mammary tissue and aberrantly regulated in breast cancer. At physiological levels, KLK6 functions as a suppressor of breast cancer, while its aberrant overexpression (> 50‐fold higher than normal) is characteristic of a subset of breast cancers and has been linked to accelerated growth of primary breast tumors in severe combined immunodeficiency mice (Pampalakis et al. Cancer Res 2009, 69, 3779). Here, we investigated the molecular mechanisms underlying the concentration‐dependent functions of KLK6 by comparing MDA‐MB‐231 stable transfectants expressing increasing levels of KLK6 in in vitro and in vivo tumorigenicity assays (soft agar, xenograft growth, tail vein metastasis). Quantitative proteomics was applied to identify proteins that are altered upon re‐expression of KLK6 in MDA‐MB‐231 at normal or constitutive levels. Overexpression of KLK6 is associated with increased metastatic ability of breast cancer cells into lungs, increased expression of certain S100 proteins (S100A4, S100A11) and keratins (KRT), and downregulation of the apoptosis‐related proteases CASP7 and CASP8, and RABs. On the other hand, KLK6 re‐expression at physiological levels leads to inhibition of lung metastases associated with suppression of S100 proteins (S100A4, S100A10, S100A13, S100A16) and induced CASP7 and CASP8 expression. As this is the first report that KLK6 expression is associated with S100 proteins, caspases, RABs, and KRTs, we validated this finding in clinical datasets. By integrating proteomics and microarray data from breast cancer patients, we generated two composite scores, KLK6 + S100B‐S100A7 and KLK6 + S100B‐S100A14‐S100A16, to predict long‐term survival of breast cancer patients. We present previously unknown pathways implicating KLK6 in breast cancer. The findings promise to aid our understanding of the functional roles of KLK6 in breast cancer and may yield new biomarkers for the cancer types in which KLK6 is known to be aberrantly upregulated.

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Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6

Vita

Smits²,

Hurk³

et al. 2019

ChemMedChem

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Kallikrein‐related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high‐throughput screen within the European Lead Factory program. Structure‐guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)‐3‐(4‐carbamimidoylphenyl)‐N‐((S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) and 34 ((5R)‐3‐(6‐carbamimidoylpyridin‐3‐yl)‐N‐((1S)‐1‐(naphthalen‐1‐yl)propyl)‐2‐oxooxazolidine‐5‐carboxamide) have single‐digit nanomolar potency against KLK6, with over 25‐fold and 100‐fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6‐dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.

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

Cited by 46 publications

References 55 publications

Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

Expression of Kallikrein-Related Peptidase 6 in Primary Mucosal Malignant Melanoma of the Head and Neck

Biochemical pathways mediated by KLK6 protease in breast cancer

Synthesis and Structure‐Activity Relationships of N‐(4‐Benzamidino)‐Oxazolidinones: Potent and Selective Inhibitors of Kallikrein‐Related Peptidase 6

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