Generation and phenotyping of K5-Kallikrein 5 transgenic mice

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Matriptase, a type II transmembrane serine protease, induces malignant transformation through proteolytic activation of pro-HGF and PAR-2, which leads to activation of PI3K-AKT-mTOR and NFºB signaling, respectively, in epithelial stem cells. Lympho-Epithelial Kazal-Type-related Inhibitor (LEKTI) was shown to inhibit matriptase-driven proteolytic pathway through direct inhibition of kallikreins in terminal epithelial differentiation; and preliminary data from our laboratory shows that LEKTI is expressed by well-differentiated tumor cells in human oral squamous cell carcinoma (OSCC). Thus, we have hypothesized that matriptase-driven malignant transformation is inhibited by LEKTI in squamous cell carcinoma (SCC). To induce the simultaneous expression of matriptase and LEKTI in mouse epithelial stem cells, transgenic mice expressing either matriptase or LEKTI under the control of keratin 5 promoter were interbred. Our unpublished results show a prominent rescue of K5-Matriptase premalignant phenotype in the double transgenic mice. More importantly, in DMBA-induced squamous cell carcinogenesis, LEKTI expression delays matriptase-driven tumor formation and progression. Since LEKTI is unable to directly inhibit matriptase, LEKTI inhibition could occur through the inhibition of epithelial kallikreins. IHC analysis of adult mice skin showed kallikrein 5 (KLK5) is increased in K5-Mat mice while LEKTI co-expression was able to revert this phenotype. These results indicate KLK5 might be a substrate for matriptase in SCCs. Therefore we aim to design and develop transgenic mice expressing KLK5 in epithelial stem cells to further investigate this novel mechanism of LEKTI inhibition in matriptase-driven carcinogenesis in vivo. (AU)