Exploring Connexin Mimetic Peptides in Strategies of Prevention and Treatment of Squamous Cell Carcinomas induced by UV radiation and other cutaneous neoplasms: in vitro and in vivo studies.

• Grant number: 23/15620-6
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2024
• End date: April 30, 2026
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Animal Pathology
• Principal Investigator: Maria Lucia Zaidan Dagli
• Grantee: Maria Lucia Zaidan Dagli
• Host Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated scholarship(s): 24/21066-4 - Evaluation of connexin expression, their subcellular localization, and effects of treatment with connexin mimetic and non-mimetic peptides in vivo., BP.TT; 24/05955-3 - Evaluation of connexin expression, its subcellular localization, and effects of treatment with mimetic and non-mimetic peptides for connexins in vivo., BP.TT

Abstract

Squamous cell carcinoma (SCC) is a highly aggressive and prevalent non-melanoma skin cancer (NMSC) in both humans and other animals. The main risk factor for SCC is ultraviolet radiation (UV), especially UVB, which induces direct damage to DNA, among other mechanisms. Skin carcinogenesis, and the development of SCC, consists of multiple stages, which makes it possible to interfere in the process with a view to preventing it. Numerous genetic and epigenetic changes have been demonstrated in SCC. Changes in gap junctions and connexins have been detected in several chemical carcinogenesis studies; however, there are no reports in the literature about changes in these junctions in UV-induced skin carcinogenesis and SCC. Connexin mimetic peptides are a class of synthetic peptides that have potential therapeutic uses in a variety of pathological processes where there are alterations in the capacity for intercellular communication. A therapeutic peptide that acts on Cx43, the ±CT1 peptide, provides the restoration of gap junctions, and has shown inhibitory effects on the growth of human mammary neoplastic cells and canine oral melanoma. The peptide Rotigaptide ZP-123 will also be tested, which demonstrated an increase in cardiac conductance, but there is little information about its mechanism of action. The objective of this project is to evaluate the preventive and antineoplastic effects of connexin-mimetic peptides in squamous cell carcinoma induced, in vitro, by successive exposure of human epithelial cells to ultraviolet radiation, and in vivo, in SKH mice exposed to UV. To this end, an in vitro model of SCC development will be used, using immortalized human epidermal keratinocytes (HaCaT) subjected to UV radiation. The expression and subcellular localization of connexins 43, 31.1, 26 and 32, in addition to E-cadherin, in HaCaT cells will be evaluated, before and after successive exposure to UVB radiation, HaCaT cells will be subjected to the same UV carcinogenesis model and treated with the ±CT1 peptide, using the reverse peptide as a control. The resulting CCEs will be xenotransplanted into immunodeficient mice and the potential antineoplastic effects of the ±CT1 peptide will be tested in these animals. The skin carcinogenesis model in SKH1 mice will be developed by exposure to UV radiation for 20-25 weeks, according to a protocol pre-established in the literature. The development of cutaneous neoplasms in vivo will be evaluated in the presence or absence of connexin-mimetic peptides. In this way, it is expected to evaluate the expression of connexins, their changes during carcinogenesis, and the preventive and antineoplastic effects of the ±CT1 mimetic peptide in the development of SCC induced by UV exposure, as well as other UV-induced cutaneous neoplasms. (AU)