Role of kallikrein 14 (KLK14) in oral squamous cell carcinogenesis

• Grant number: 21/14597-5
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2022
• End date: April 30, 2024
• Field of knowledge: Health Sciences - Dentistry
• 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 researchers: Leandro Machado Colli

Abstract

Head and neck squamous cell carcinoma (HNSCC), including carcinomas of the oral cavity (OSCC), remains a challenging cancer to treat with no improvement in survival rates over the past 50 years. Thus, there is an urgent need to discover more reliable therapeutic targets and biomarkers for this disease. Kallikrein 5 (KLK5) is a member of the tissue kallikrein family implicated in OSCC development. Our laboratory has recently shown (Alves et al., 2020) that the expression of KLK5 with relative to its cognate inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI) is a strong prognostic marker in OSCC. Increased KLK5 to LEKTI expression in human patient samples was associated with poor prognosis: results that we were able to recapitulate in a CRISPR/Cas9 genetically modified OSCC model. Additional work from our laboratory has also unveiled an inhibitory role for LEKTI in matriptase-dependent carcinogenesis (da Silva et al., 2021). Matriptase is a type II transmembrane serine protease that promotes malignant transformation in OSCC through proteolytic activation of pro-hepatocyte growth factor (pro-HGF) and proteinase-activated receptor-2 (PAR-2). We have observed that LEKTI delays matriptase-driven tumor formation and progression through KLK5 inhibition in a mouse model of HNSCC. Collectively, our results highlight the pivotal role of serine proteases and their inhibitors in OSCC and their potential for serving as biomarkers and therapeutic targets. To continue with our studies, we will further investigate the signaling pathways of KLK5 and of the unexplored kallikrein 14 (KLK14). KLK14 is overexpressed in cancer and activated by KLK5. Importantly, we hypothesize that KLK5-dependent OSCC formation occurs through the activation of KLK14 signaling pathway. Our hypothesis will be tested in vivo and in vitro using: (i) genetically modified cells using CRISPR/Cas9 tools; (ii) RNA sequencing technology to discover new molecular players and dissect proteolytic pathways involved in OSCCs; (iii) genetic epistasis analysis, through the generation of KLK14 transgenic mice; and (iv) DMBA challenging of mice in order to evaluate carcinoma formation and progression in wild type versus transgenic mice. (AU)