Genetic epistasis analysis of matriptase-depedent proteolytic pathway in head and neck cancer

• Grant number: 14/06316-2
• Support type: Research Grants - Young Investigators Grants
• Duration: August 01, 2014 - January 31, 2019
• Field of knowledge: Biological Sciences - Genetics
• Principal researcher: Katiuchia Uzzun Sales
• Grantee: Katiuchia Uzzun Sales
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 16/13228-8 - Genetic study of LEKTI superexpression in HNSCC mouse model, BP.PD; 16/16350-9 - Study of serine protease TMPRSS11A signaling pathway using genetically modified mice, BP.IC; 16/13343-1 - Protein expression encoded by TMPRSS11A gene and its involvement in the formation of carcinoma, BP.IC; + associated scholarships 16/16715-7 - Regulation of hepatocyte growth factor activator inhibitor-1 (HAI-1) activity by HPV 16 oncogenes E6 and E7, BP.MS; 15/06603-4 - LEKTI: a new prognostic marker in oral carcinoma, BP.IC; 14/14311-0 - GENETIC EPISTASIS ANALYSIS OF MATRIPTASE-DEPENDENT PROTEOLYTIC PATHWAY IN HEAD AND NECK CANCER, BP.JP - associated scholarships

Abstract

Head and neck cancer (HNSCC) is the sixth most common cancer worldwide, with an estimated burden of approximately 500,000 cases/year. Matriptase, a protease belonging to the type II transmembrane serine proteases (TTSPs), is unique among tumor-associated proteases in that epithelial stem cell expression suffices to induce malignant transformation. It has been recently shown that PI3K-Akt-mTor signaling, elicited by proteolytic activation of pro-hepatocyte growth factor, is one molecular pathway by which matriptase promotes malignant conversion. A second and essential component of matriptase-mediated oncogenesis is the upregulation of NFkappaB-induced inflammatory chemokines and cytokines that are dependent on the PAR-2 (protease receptor-2) proteolytic cleavage by matriptase. Moreover, HPV (human papiloma virus)-associated HNSCC carcinomas have been increasing and it has become an important etiologic factor of this disease. Moreover, its oncogenic potential arises with the dysregulated expression of two viral oncoproteins: E6 and E7. Clinically, HPV-positive tumors are less agressive. In addition, recently, it has been shown a positive correlation between the immuno expression of the cognate inhibitor of matriptase, HAI-1 (hepatocyte growth factor activator inhibitor), and the better prognosis of this disease in cervical carcinomas (that are mostly caused by HPV infection). Using in vivo genetic epistasis analysis, evaluating histological and molecular signature present in murine and human biopsies of pre-malignant and malignant lesions, and developing in vitro cell-based assays; we aim to evaluate whether there is a diference, regarding matriptase-dependent proteolytic pathway target genes, in malignant and pre-malignant lesions that are associated with HPV-induced transformation. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MARCELINO DA SILVA, ELAINE ZAYAS; DE CAMPOS FRAGA-SILVA, THAIS FERNANDA; YUAN, YAO; ALVES, MARCIA GAIAO; PUBLIO, GABRIEL AZEVEDO; DA FONSECA, CAROL KOBORI; KODAMA, MARCIO HIDEKI; VIEIRA, GABRIEL VILIOD; CANDIDO, MARINA FERREIRA; RAMOS INNOCENTINI, LARA MARIA ALENCAR; MIRANDA, MATEUS GONCALVES; DA SILVA, ALFREDO RIBEIRO; ALVES-FILHO, JOSE CARLOS; DEPERON BONATO, VANIA LUIZA; IGLESIAS-BARTOLOME, RAMIRO; SALES, KATIUCHIA UZZUN. Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis. CANCERS, v. 13, n. 17 SEP 2021. Web of Science Citations: 0.

ALVES, MARCIA GAIAO; KODAMA, MARCIO HIDEKI; MARCELINO DA SILVA, ELAINE ZAYAS; MARTINELLI GOMES, BRUNO BELMONTE; ALVES DA SILVA, RODRIGO ALBERTO; VIEIRA, GABRIEL VILIOD; ALVES, VANI MARIA; DA FONSECA, CAROL KOBORI; SANTANA, ANA CAROLINA; CECILIO, NERRY TATIANA; ALEXANDRE COSTA, MARA SILVIA; JAMUR, MARIA CELIA; OLIVER, CONSTANCE; CUNHA, THIAGO MATTAR; BUGGE, THOMAS H.; BRAZ-SILVA, PAULO HENRIQUE; COLLI, LEANDRO M.; SALES, KATIUCHIA UZZUN. Relative expression of KLK5 to LEKTI is associated with aggressiveness of oral squamous cell carcinoma. TRANSLATIONAL ONCOLOGY, v. 14, n. 1 JAN 2021. Web of Science Citations: 0.