ANALYSIS OF THE KALYKREIN 5/KALYKREIN 14 (KLK5/KLK14) PROTEOLYTIC PATHWAY IN HEAD AND NECK CARCINOMA

• Grant number: 25/03291-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2025
• End date: January 31, 2029
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Katiuchia Uzzun Sales
• Grantee: Mateus Gonçalves Miranda
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 24/10667-7 - KLK5-KLK14-hippo signaling in the formation and progression of Head and Neck Carcinoma, AP.R

Abstract

Head and neck squamous cell carcinomas (HNSCC) are malignant neoplasia with a high incidence worldwide, which is about 890,000 people affected annually. Approximately 450,000 deaths in the world yearly are a consequence of this devastating disease. The treatment, however, still suffers significantly from no specificity. Proteases, in general, play a relevant role in the transformation and spread of malignant neoplasms. For example, there is kallikrein 5 (KLK5), a member of the tissue kallikrein family, which participates in the pathogenesis of HNSCC and other solid tumors (Vieira GV et al., 2022a). Recently, we have shown that the increased relative expression of KLK5 to its cognate inhibitor, LEKTI, in human HNSCC samples was related to poor prognosis: these results were reproduced in a genetically modified HNSCC model using the CRISPR-Cas9 technique (Alves, MG et al., 2021). We have also shown that the inhibitory role of LEKTI in matriptase-dependent carcinogenesis occurs through KLK5 inhibition (da Silva, EZM et al., 2021). Matriptase, a type II transmembrane serine protease, promotes malignant transformation in HNSCC by activating hepatocyte growth factor (pro-HGF) and protease-activated receptor 2 (PAR-2), amongst other substrates. Additionally, in a manuscript in preparation, we have found that the absence of KLK5 and KLK7 in HPV-positive lesions genetically modulates kallikrein 14 (KLK14) (Vieira GV et al., 2022b, manuscript attached to SAGE). This modulation of KLK14 was responsible for rescuing the HPV-dependent phenotype in transgenic mice expressing HPV oncogenes under the keratin 14 (K14) promoter. As a continuation, in this doctorate project, we will investigate in detail the signaling pathways of KLK5 and the yet unexplored kallikrein 14 (KLK14) in HNSCC. Significantly and based on the solid results from our laboratory (Vieira GV et al., 2022a; Vieira GV et al., 2022b; Alves, MG et al., 2021; da Silva, EZM et al., 2021), we hypothesize that KLK5-dependent HNSCC formation takes place through activation of the KLK14 and Hippo signaling pathways. This hypothesis will be tested, in vivo, through epistatic gene interaction, with the generation and use of transgenic mice whose target genes are KLK5 (Klk5) and KLK14 (Klk14). Furthermore, tissue biology experiments will be carried out, focusing on discovering new cellular targets and dissecting the proteolytic pathways dependent on KLK5 and KLK14, and involved in the HNSCCs. It is essential to mention the potential of these proteases in developing biomarkers and therapeutic targets since they are proteases secreted into the extracellular environment and, therefore, are pharmacologically easy to access. (AU)