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Functional consequences of the STAT3 c.-1937C>G genetic variant on cutaneous melanoma

Grant number: 19/16776-4
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): September 20, 2019
Effective date (End): January 19, 2020
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Carmen Silvia Passos Lima
Grantee:Gabriela Vilas Bôas Gomez
Supervisor abroad: Juan Angel Recio
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Local de pesquisa : Vall d'Hebron Research Institute (VHIR), Spain  
Associated to the scholarship:16/25407-4 - Influence of polymorphisms in JAK/STAT pathway genes on the susceptibility and clinicopathological aspects of patients with cutaneous melanoma, BP.DR

Abstract

Cutaneous melanoma (CM) is a serious public health problem due to its high metastatic potential and high mortality rate. The Janus kinase/signal tranducer (JAK/STAT) signaling pathway regulates the development, progression and metastatic potential of the tumor. The STAT3 protein is encoded by polymorphic genes in humans and thus it is possible for normal individuals to present inherited differences in the functionality of this pathway, with consequent different risks for the occurrence of CM, different clinicopathological aspects of the tumor and prognosis. We found in the initial part of this project that individuals with the CC genotype of STAT3 c.-1937C> G were under 2.0 times greater risks of developing CM (CI 95%: 1.06-2.63, P= 0.02). In a genetically modified melanoma cell line (SK-MEL-28) to present the distinct genotypes of this single-nucleotide variant (SNV), we observed a 30% increase in the promoter activity of the gene and increase of mRNA in cells with the CC genotype compared to GG genotype, but we do not know the consequences of the SNV in the codified protein. The next objective of this project (to be developed in another service) is to verify if SNV STAT3 c-1937C>G influence the expression and function of STAT3 proteins. Quantification of proteins will be complemented by western blotting and studies of apoptosis and cell cycle will be performed in SK-MEL-28 melanoma cell line genetically modified to present the different genotypes (CC and GG). Comparisons of protein expression will be calculated using t-tests and ANOVA or Mann-Whitney and Kruskal-Wallis tests. We believe that results may contribute to a better understanding of the pathophysiology of CM and to identify individuals at high risk for tumor occurrence or even more aggressive disease.