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Genetic study of Klk5's role in matriptase proteolytic pathway in head and neck squamous cell carcinoma

Grant number: 19/23978-2
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2020
Effective date (End): December 31, 2020
Field of knowledge:Biological Sciences - Genetics - Animal Genetics
Principal Investigator:Elaine Zayas Marcelino da Silva
Grantee:Mateus Gonçalves Miranda
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Head and Neck Carcinomas (HNSCC) comprise predominantly squamous cell carcinomas of the oral cavity, larynx and pharynx. HNSCCs are the sixth most common type of cancer and affects over 550.000 patients annually. Matriptase, a type 2 transmembrane serine protease, induces malignant transformation when expressed in epithelial stem cells. Proteolytic activation of pro-HGF and the PI3K-Akt-mTor signaling pathway is one of the mechanisms involved in the malignant transformation. Super expression of inflammatory cytokines mediated by NFkB activation is another essential component for transformation. In addition, matriptase play a role in the activation Klk5 and Klk7 which are then inhibited by LEKTI during terminal differentiation of keratinocytes in the epidermis. Unpublished data from our laboratory show that LEKTI is downregulated in biopsies of human oral squamous cell carcinomas. We also found that the matriptase proteolytic pathway is partially inhibited by LEKTI in SCC. In a mouse model of matriptase driven SCC induced by DMBA, LEKTI co-expression with matriptase in basal keratinocytes delays the onset and inhibits progression of malignant lesions. Therefore, LEKTI acts as a suppressor of matriptase driven SCC. Since LEKTI is unable to directly inhibit matriptase, epithelial Klks are potential targets for this inhibition in SCC. In fact, IHC analysis of K5-Mat+/0 epidermis shows an altered expression of Klk5 and this phenotype is rescued when LEKTI is co-expressed (K5-Mat+/0/LEKTI+/0). To clarify the role of Klk5 in the proteolytic pathway of matriptase in SCC in vivo, transgenic mice expressing pro-Klk5 in basal keratinocytes (K5-Klk5+/0) and knockout mice for Klk5 (Klk5-/-) were generated (in collaboration with NIDCR at NIH during BEPE of Dr. Elaine). In this Project we aim to breed Klk5-/- mice with K5-Mat+/0 to investigate if matriptase driven SCC is dependent on Klk5. Our studies will rely on in vivo genetic manipulations, and histological and molecular analysis of tissues obtained from the experimental models.