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Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis
SIMPLE SUMMARY: Head and neck squamous cell carcinomas (HNSCC) are among the most common cancers worldwide. In contrast to the advances in prevention and treatment of other types of cancer, the five-year survival rate for HNSCC is only about 50% and it has not changed for the past 50 years. This poo...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431081/ https://www.ncbi.nlm.nih.gov/pubmed/34503205 http://dx.doi.org/10.3390/cancers13174395 |
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author | da Silva, Elaine Zayas Marcelino Fraga-Silva, Thais Fernanda de Campos Yuan, Yao Alves, Márcia Gaião Publio, Gabriel Azevedo da Fonseca, Carol Kobori Kodama, Márcio Hideki Vieira, Gabriel Viliod Candido, Marina Ferreira Innocentini, Lara Maria Alencar Ramos Miranda, Mateus Gonçalves da Silva, Alfredo Ribeiro Alves-Filho, Jose Carlos Bonato, Vania Luiza Deperon Iglesias-Bartolome, Ramiro Sales, Katiuchia Uzzun |
author_facet | da Silva, Elaine Zayas Marcelino Fraga-Silva, Thais Fernanda de Campos Yuan, Yao Alves, Márcia Gaião Publio, Gabriel Azevedo da Fonseca, Carol Kobori Kodama, Márcio Hideki Vieira, Gabriel Viliod Candido, Marina Ferreira Innocentini, Lara Maria Alencar Ramos Miranda, Mateus Gonçalves da Silva, Alfredo Ribeiro Alves-Filho, Jose Carlos Bonato, Vania Luiza Deperon Iglesias-Bartolome, Ramiro Sales, Katiuchia Uzzun |
author_sort | da Silva, Elaine Zayas Marcelino |
collection | PubMed |
description | SIMPLE SUMMARY: Head and neck squamous cell carcinomas (HNSCC) are among the most common cancers worldwide. In contrast to the advances in prevention and treatment of other types of cancer, the five-year survival rate for HNSCC is only about 50% and it has not changed for the past 50 years. This poor prognosis is mainly due to a shortage of suitable markers for early detection, delayed diagnosis and/or referral, and ineffectiveness of chemotherapy. The aim of this study was to explore the inhibitory role of LEKTI in matriptase-dependent squamous cell carcinogenesis and to investigate additional players operating in this pathway. We found that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. This knowledge can contribute for the development of future targeted therapy in HNSCC. ABSTRACT: Head and neck squamous cell carcinoma remains challenging to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for HNSCC. Matriptase, a type-II transmembrane serine protease, induces malignant transformation in epithelial stem cells through proteolytic activation of pro-HGF and PAR-2, triggering PI3K-AKT-mTOR and NFKB signaling. The serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) inhibits the matriptase-driven proteolytic pathway, directly blocking kallikreins in epithelial differentiation. Hence, we hypothesized LEKTI could inhibit matriptase-dependent squamous cell carcinogenesis, thus implicating kallikreins in this process. Double-transgenic mice with simultaneous expression of matriptase and LEKTI under the keratin-5 promoter showed a prominent rescue of K5-Matriptase(+/0) premalignant phenotype. Notably, in DMBA-induced SCC, heterotopic co-expression of LEKTI and matriptase delayed matriptase-driven tumor incidence and progression. Co-expression of LEKTI reverted altered Kallikrein-5 expression observed in the skin of K5-Matriptase(+/0) mice, indicating that matriptase-dependent proteolytic pathway inhibition by LEKTI occurs through kallikreins. Moreover, we showed that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. Collectively, our data identify a third signaling pathway for matriptase-dependent carcinogenesis in vivo. These findings are critical for the identification of more reliable biomarkers and effective therapeutic targets in Head and Neck cancer. |
format | Online Article Text |
id | pubmed-8431081 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84310812021-09-11 Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis da Silva, Elaine Zayas Marcelino Fraga-Silva, Thais Fernanda de Campos Yuan, Yao Alves, Márcia Gaião Publio, Gabriel Azevedo da Fonseca, Carol Kobori Kodama, Márcio Hideki Vieira, Gabriel Viliod Candido, Marina Ferreira Innocentini, Lara Maria Alencar Ramos Miranda, Mateus Gonçalves da Silva, Alfredo Ribeiro Alves-Filho, Jose Carlos Bonato, Vania Luiza Deperon Iglesias-Bartolome, Ramiro Sales, Katiuchia Uzzun Cancers (Basel) Article SIMPLE SUMMARY: Head and neck squamous cell carcinomas (HNSCC) are among the most common cancers worldwide. In contrast to the advances in prevention and treatment of other types of cancer, the five-year survival rate for HNSCC is only about 50% and it has not changed for the past 50 years. This poor prognosis is mainly due to a shortage of suitable markers for early detection, delayed diagnosis and/or referral, and ineffectiveness of chemotherapy. The aim of this study was to explore the inhibitory role of LEKTI in matriptase-dependent squamous cell carcinogenesis and to investigate additional players operating in this pathway. We found that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. This knowledge can contribute for the development of future targeted therapy in HNSCC. ABSTRACT: Head and neck squamous cell carcinoma remains challenging to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for HNSCC. Matriptase, a type-II transmembrane serine protease, induces malignant transformation in epithelial stem cells through proteolytic activation of pro-HGF and PAR-2, triggering PI3K-AKT-mTOR and NFKB signaling. The serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI) inhibits the matriptase-driven proteolytic pathway, directly blocking kallikreins in epithelial differentiation. Hence, we hypothesized LEKTI could inhibit matriptase-dependent squamous cell carcinogenesis, thus implicating kallikreins in this process. Double-transgenic mice with simultaneous expression of matriptase and LEKTI under the keratin-5 promoter showed a prominent rescue of K5-Matriptase(+/0) premalignant phenotype. Notably, in DMBA-induced SCC, heterotopic co-expression of LEKTI and matriptase delayed matriptase-driven tumor incidence and progression. Co-expression of LEKTI reverted altered Kallikrein-5 expression observed in the skin of K5-Matriptase(+/0) mice, indicating that matriptase-dependent proteolytic pathway inhibition by LEKTI occurs through kallikreins. Moreover, we showed that Kallikrein-5 is necessary for PAR-2-mediated IL-8 release, YAP1-TAZ/TEAD activation, and matriptase-mediated oral squamous cell carcinoma migration. Collectively, our data identify a third signaling pathway for matriptase-dependent carcinogenesis in vivo. These findings are critical for the identification of more reliable biomarkers and effective therapeutic targets in Head and Neck cancer. MDPI 2021-08-31 /pmc/articles/PMC8431081/ /pubmed/34503205 http://dx.doi.org/10.3390/cancers13174395 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article da Silva, Elaine Zayas Marcelino Fraga-Silva, Thais Fernanda de Campos Yuan, Yao Alves, Márcia Gaião Publio, Gabriel Azevedo da Fonseca, Carol Kobori Kodama, Márcio Hideki Vieira, Gabriel Viliod Candido, Marina Ferreira Innocentini, Lara Maria Alencar Ramos Miranda, Mateus Gonçalves da Silva, Alfredo Ribeiro Alves-Filho, Jose Carlos Bonato, Vania Luiza Deperon Iglesias-Bartolome, Ramiro Sales, Katiuchia Uzzun Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis |
title | Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis |
title_full | Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis |
title_fullStr | Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis |
title_full_unstemmed | Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis |
title_short | Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis |
title_sort | kallikrein 5 inhibition by the lympho-epithelial kazal-type related inhibitor hinders matriptase-dependent carcinogenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431081/ https://www.ncbi.nlm.nih.gov/pubmed/34503205 http://dx.doi.org/10.3390/cancers13174395 |
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