Relative expression of KLK5 to LEKTI is associated with aggressiveness of oral squamous cell carcinoma

Márcia Gaião Alves; Márcio Hideki Kodama; Elaine Zayas Marcelino da Silva; Bruno Belmonte Martinelli Gomes; Rodrigo Alberto Alves da Silva; Gabriel Viliod Vieira; Vani Maria Alves; Carol Kobori da Fonseca; Ana Carolina Santana; Nerry Tatiana Cecílio; Mara Silvia Alexandre Costa; Maria Célia Jamur; Constance Oliver; Thiago Mattar Cunha; Thomas H. Bugge; Paulo Henrique Braz-Silva; Leandro M. Colli; Katiuchia Uzzun Sales

Translational Oncology (Jan 2021)

Relative expression of KLK5 to LEKTI is associated with aggressiveness of oral squamous cell carcinoma

Márcia Gaião Alves,
Márcio Hideki Kodama,
Elaine Zayas Marcelino da Silva,
Bruno Belmonte Martinelli Gomes,
Rodrigo Alberto Alves da Silva,
Gabriel Viliod Vieira,
Vani Maria Alves,
Carol Kobori da Fonseca,
Ana Carolina Santana,
Nerry Tatiana Cecílio,
Mara Silvia Alexandre Costa,
Maria Célia Jamur,
Constance Oliver,
Thiago Mattar Cunha,
Thomas H. Bugge,
Paulo Henrique Braz-Silva,
Leandro M. Colli,
Katiuchia Uzzun Sales

Affiliations

Márcia Gaião Alves: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Márcio Hideki Kodama: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Elaine Zayas Marcelino da Silva: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil; Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
Bruno Belmonte Martinelli Gomes: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Rodrigo Alberto Alves da Silva: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Gabriel Viliod Vieira: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Vani Maria Alves: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Carol Kobori da Fonseca: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Ana Carolina Santana: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Nerry Tatiana Cecílio: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
Mara Silvia Alexandre Costa: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Maria Célia Jamur: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Constance Oliver: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil
Thiago Mattar Cunha: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
Thomas H. Bugge: Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
Paulo Henrique Braz-Silva: Department of Stomatology, School of Dentistry, University of Sao Paulo, Sao Paulo, SP – Brazil; Laboratory of Virology, Institute of Tropical Medicine of Sao Paulo, School of Medicine, University of Sao Paulo, Sao Paulo, SP – Brazil
Leandro M. Colli: Department of Image Science, Hematology and Medical Oncology, Ribeirao Preto Medical School, University of Sao Paulo, SP – Brazil
Katiuchia Uzzun Sales: Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil; Corresponding author.

Journal volume & issue: Vol. 14, no. 1
p. 100970

Abstract

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Background: Oral squamous cell carcinoma (OSCC) remains a challenging cancer to treat despite all the advances of the last 50 years. Kallikrein 5 (KLK5) is among the serine proteases implicated in OSCC development. However, whether the activity of KLK5 promotes carcinogenesis is still controversial. Moreover, knowledge regarding the role of the KLK5 cognate inhibitor, Lympho-Epithelial Kazal-Type related Inhibitor (LEKTI), in OSCC is scarce. We have, thus, sought to investigate the importance of KLK5 and LEKTI expression in premalignant and malignant lesions of the oral cavity. Methods: KLK5 and LEKTI protein expression was evaluated in 301 human samples, which were comprised of non-malignant and malignant lesions of the oral cavity. Moreover, a bioinformatic analysis of the overall survival rate from 517 head and neck squamous cell carcinoma (HNSCC) samples was performed. Additionally, to mimic the uncovered KLK5 to serine peptidase inhibitor (SPINK5) imbalance, the KLK5 gene was abrogated in an OSCC cell line using CRISPR-Cas9 technology. The generated cell line was then used for in vivo and in vitro carcinogenesis related experiments. Results: LEKTI was found to be statistically downregulated in OSCCs, with increased KLK5/SPINK5 mRNA ratio being associated with a shorter overall survival (p = 0.091). Indeed, disruption of KLK5 to SPINK5 balance through the generation of KLK5 null OSCC cells led to smaller xenografted tumors and statistically decreased proliferation rates following multiple time points of BrdU treatment in vitro. Conclusion: The association of increased enzyme/inhibitor ratio with poor prognosis indicates KLK5 to SPINK5 relative expression as an important prognostic marker in OSCC.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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