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

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)

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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)
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; et al. Relative expression of KLK5 to LEKTI is associated with aggressiveness of oral squamous cell carcinoma. TRANSLATIONAL ONCOLOGY, v. 14, n. 1, . (14/06316-2, 16/13228-8, 16/16715-7)
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; et al. Kallikrein 5 Inhibition by the Lympho-Epithelial Kazal-Type Related Inhibitor Hinders Matriptase-Dependent Carcinogenesis. CANCERS, v. 13, n. 17, . (17/24730-9, 16/13228-8, 14/06316-2)
VIEIRA, GABRIEL VILIOD; SOMERA DOS SANTOS, FERNANDA; LEPIQUE, ANA PAULA; DA FONSECA, CAROL KOBORI; INNOCENTINI, LARA MARIA ALENCAR RAMOS; BRAZ-SILVA, PAULO HENRIQUE; QUINTANA, SILVANA MARIA; SALES, KATIUCHIA UZZUN. Proteases and HPV-Induced Carcinogenesis. CANCERS, v. 14, n. 13, p. 25-pg., . (14/06316-2, 19/04896-5, 18/16989-5)

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