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Genetic study of LEKTI superexpression in HNSCC mouse model

Grant number: 16/13228-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2016
Effective date (End): October 25, 2020
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Katiuchia Uzzun Sales
Grantee:Elaine Zayas Marcelino da Silva
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/06316-2 - Genetic epistasis analysis of matriptase-depedent proteolytic pathway in head and neck cancer, AP.JP
Associated scholarship(s):17/24730-9 - Generation and phenotyping of K5-Kallikrein 5 transgenic mice, BE.EP.PD

Abstract

Head and neck cancer comprises predominantly squamous cell carcinomas and affects the oral cavity, larynx, and pharynx. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with 550.000 new cases every year. Matriptase, a type II transmembrane serine protease, induces malignant transformation when expressed in epithelial stem cells. 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 transformation. Another essential component of matriptase-mediated oncogenesis is the upregulation of NFkB-induced inflammatory cytokines that are dependent on the PAR-2 proteolytic cleavage by matriptase. Moreover, it has been demonstrated that matriptase-dependent activation of kallikreins 5 and 7, during terminal differentiation of keratinocytes, is inhibited by the serine protease inhibitor LEKTI. Preliminary data from our laboratory show that LEKTI is predominantly expressed by well differentiated cells, in human oral squamous cell carcinomas. Moreover, other preliminary results from our group suggest that LEKTI expression is upregulated in the epithelia, when matriptase is expressed in epithelial stem cells. Therefore, we aim on testing the hypothesis in which matriptase-dependent proteolytic pathway is inhibited by LEKTI in carcinomas. In order to test this hypothesis, we have been using transgenic mice that express LEKTI and matriptase, under the control of keratin 5 promoter (K5-LEKTI and K5-Mat mice, respectively). Preliminary data has been very promising and shows a 100% rescue of K5-Mat premalignant phenotype in double transgenic mice (K5-LEKTI/K5-Mat), when K5-LEKTI mice are bred to K5-Mat mice. Since LEKTI is unable to directly inhibit matriptase, we hypothesized that there is a third matriptase target, in addition to pro-HGF and PAR-2, in malignant epithelial neoplasia. In this respect, LEKTI inhibition of matriptase-dependent proteolytic pathway could occur, for instance, through the inhibition of epithelial kallikreins. Using in vivo genetic manipulation, accompanied by histological evaluation and molecular signature analysis of murine biopsies, in addition to in vitro cell-based assays; we aim to uncover the genetic and cellular mechanisms involved in matriptase-dependent malignant transformation, with emphasis on the inhibitory role of LEKTI. The results obtained in this study will be associated with results of other current project of our group where the expression of LEKTI and epithelial kallikreins are being immunohistochemically evaluated in biopsies of human oral squamous cell carcinomas.