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Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent
Elaine Zayas Marcelino da Silva1, Thais Fernanda de Campos Fraga-Silva2, Yao Yuan3
1Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, SP, Brazil.
Cancers
|September 10, 2021
Summary
Lympho-epithelial Kazal-type-related inhibitor (LEKTI) shows promise in treating head and neck squamous cell carcinoma (HNSCC). LEKTI inhibits matriptase, a key driver of HNSCC, by targeting kallikreins, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) treatment has stagnated, lacking effective therapeutic targets and biomarkers.
- Matriptase, a serine protease, drives HNSCC by activating signaling pathways like PI3K-AKT-mTOR and NFKB.
- The inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) targets matriptase's proteolytic activity.
Purpose of the Study:
- To investigate the potential of LEKTI in inhibiting matriptase-dependent squamous cell carcinogenesis.
- To elucidate the role of kallikreins in HNSCC development and progression.
- To identify novel therapeutic targets and biomarkers for HNSCC.
Main Methods:
- Utilized double-transgenic mice expressing matriptase and LEKTI under the keratin-5 promoter.
- Investigated the effects of LEKTI co-expression on DMBA-induced SCC progression and tumor incidence.
- Analyzed kallikrein expression, PAR-2 activation, IL-8 release, and YAP1-TAZ/TEAD signaling.
Main Results:
- LEKTI expression rescued the premalignant phenotype in K5-Matriptase mice.
- Co-expression of LEKTI delayed tumor incidence and progression in DMBA-induced SCC.
- LEKTI normalized Kallikrein-5 expression and inhibited PAR-2-mediated IL-8 release and YAP1-TAZ/TEAD activation.
Conclusions:
- LEKTI effectively inhibits matriptase-dependent carcinogenesis through modulation of kallikreins.
- Kallikrein-5 is crucial for PAR-2 signaling, YAP1-TAZ/TEAD activation, and HNSCC cell migration.
- These findings highlight a novel signaling pathway and identify LEKTI as a potential therapeutic target for HNSCC.
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