| Grant number: | 14/06316-2 |
| Support Opportunities: | Research Grants - Young Investigators Grants |
| Start date: | August 01, 2014 |
| End date: | January 31, 2019 |
| Field of knowledge: | Biological Sciences - Genetics |
| Principal Investigator: | Katiuchia Uzzun Sales |
| Grantee: | Katiuchia Uzzun Sales |
| Host 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 - 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)
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