The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer.
Cell Line, Tumor
Cell Movement
/ genetics
Cell Proliferation
/ genetics
Chromatography, High Pressure Liquid
Databases, Genetic
Down-Regulation
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Immunohistochemistry
Kallikreins
/ genetics
Male
Neoadjuvant Therapy
Neoplasm Metastasis
/ genetics
Prostatic Neoplasms
/ enzymology
Proteomics
Signal Transduction
/ genetics
Tandem Mass Spectrometry
Transcriptome
Tumor Microenvironment
/ genetics
Up-Regulation
castrate-resistant prostate cancer
kallikrein-related peptidase
metastasis
prostate cancer
protease
protease-substrate
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
23
05
2019
revised:
06
09
2019
accepted:
18
10
2019
pubmed:
21
10
2019
medline:
4
2
2021
entrez:
21
10
2019
Statut:
ppublish
Résumé
Kallikrein-related peptidase 14 (KLK14) is one of the several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumor microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analyzed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic, and in vitro assays with the goal to identify substrates, related-signaling pathways, and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neoadjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression reoccurred in patients who developed castrate-resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14 substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14-regulated genes (Interleukin 32, midkine, SRY-Box 9), particularly an involvement of the mitogen-activated protein kinase 1 and interleukin 1 receptor pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumors. Additional work is necessary to determine the benefits and implications of targeting/cotargeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment.
Identifiants
pubmed: 31630475
doi: 10.1002/1878-0261.12587
pmc: PMC6944120
doi:
Substances chimiques
KLK14 protein, human
EC 3.4.21.-
Kallikreins
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105-128Informations de copyright
© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
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