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PERLATI-SANTOS, M. Influence of R and S alleles of Slc11a1 gene in the susceptibility to skin cancer induced by 7,12-Dimethylbenz[a]anthracene. 2012. 107 p. Masters thesis (Immunology) Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, 2012. Mice selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory response differ on sensibility to carcinogenesis. AIRmin mice are significantly more sensitive to skin carcinogenesis than AIRmax mice due to the genetic background and the polymorphism of aryl hydrocarbon receptor (Ahr) gene. Furthermore,these mice have an imbalance of frequency of Slc11a1 gene alleles.The Slc11a1 gene (formerly Nramp1) polymorphism modulates macrophage activity, polymorphonuclear cells and the susceptibility to infections and autoimmune diseases. To study the interaction of resistant (R) or susceptible (S) Slc11a1 alleles with acute inflammatory reaction loci found in AIRmax and AIRmin mice, homozygous sublines for these alleles were produced. These mice were nominated AIRmax, AIRmax, AIRmin and AIRmin. The objective of this study was to investigate the difference in skin carcinogenesis sensibility induced by DMBA agent in these sublines. To induce carcinogenesis, 50μg DMBA diluted on 0.1mL acetone were applied epicutaneous to the shaved dorsal skin of mice for five consecutive days. The incidence of skin cancer was 7% in AIRmin mice and 13% in AIRmin mice, and the incidence of internal organs cancer was similar between these sublines (about 57%). AIRmax and AIRmax mice did not show skin cancer, but the incidence of internal organs cancer was 100% only in AIRmax mice. Gene expression analysis of several inflammatory cytokines and chemokines by Real Time PCR was detected in control and experimental mouse skins 48 hours after the last DMBA application. All the control mice had a basal expression of Il6, Tnfa, Il1b and Cxcl2. In DMBA treated AIRmin mice, mRNA levels of these cytokines were increased 9-, 19-, 30-and 215fold respectively. In AIRmin, these mediators were increased 11-, 4-, 6and 75-fold in relation to their controls. AIRmin differ significantly from the other sublines in some cytokines, but AIRmin presented the highest number of differentially expressed genes (P<0.001) after DMBA application. AIRmax showed a high expression of Ccl2 and Cxcl2 in the spleen. These data showed higher susceptibility to skin carcinogenesis in AIRmin than in AIRmin mice. The AIRmax animals were resistant to treatment. However, AIRmax animals showed higher susceptibility, suggesting that the S allele in the AIRmax background could influence susceptible to cancer.

Influência dos alelos R e S do gene Slc11a1 na suscetibilidade à carcinogênese de pele induzida por 7,12-dimetilbenzantraceno.