Estudo da expressão e metilação dos genes NRN1, TNFAIP3 E LRRC37A2 no câncer gástrico
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Data
2024-04-19
Autores
Santos, Leonardo Caires [UNIFESP]
Orientadores
Smith, Marília de Arruda Cardoso [UNIFESP]
Tipo
Tese de doutorado
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Resumo
O câncer gástrico (CG) tem elevada incidência e mortalidade no mundo. Estudos dos mecanismos epigenéticos em cancer têm sido realizados com frequência para um melhor entendimento da regulação da expressão gênica e para a identificação de novos biomarcadores. Foi feita uma análise de array de expressão gênica em linhagens de câncer gástrico tratadas e não tratadas com 5-azacitidina, onde encontramos 83 genes que são potencialmente modulados por metilação de DNA em linhagens celulare CG. Nós selecionamos os genes NRN1, TNFAIP3 e LRRC37A2 para serem avaliados quanto a sua expressão e metilação em tecidos gástricos tumorais e não tumorais adjacentes. O aumento da expressão de NRN1 e TNFAIP3 foi associado aos tumores avançados. Observou-se aumento da expressão de NRN1 e TNFAIP3 assossiado a menores níveis de metilação na região promotora. Redução da metilação na região promotora de NRN1 foi associada aos estágios avançados do tumor e presença de infecção por Helicobacter pylori. A diminuição da expressão de LRRC37A2 e aumento de metilação em regiões específicas do seu promotor estão associadas ao pior prognóstico. Esses resultados sugerem que alguns genes podem ser utilizados na prática clínica para estratificar pacientes que estão mais propícios a se beneficiarem por terapias epigenéticas.
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Very few therapeutic options are currently available in this neoplasia. Epigenetic manipulation of GC cell lines is a useful tool to better understand gene expression regulatory mechanisms for clinical applications. We identified 83 candidate genes modulated by DNA methylation in GC cell lines. Among the genes identified in this analysis, we selected NRN1, TNFAIP3 and LRRC37A2 to be evaluated for gene expression by RT-qPCR and DNA methylation by bisulfite DNA next-generation sequencing in pairs of GC and adjacent non-neoplastic tissue samples. Increased expression of NRN1 and TNFAIP3 was associated with advanced tumours (P < 0.05). We showed that increased NRN1 and TNFAIP3 expression seems to be regulated by DNA demethylation in GC samples: inverse correlations between themRNA and DNA methylation levels in the promoter of NRN1 (P < 0.05) and the intron of TNFAIP3 (P < 0.05) were detected. Reduced NRN1 promoter methylation was associatedwith III/IVTNMstage tumours (P = 0.03) and the presence of Helicobacter pylori infection (P = 0.02). We showed that both reduced LRRC37A2 mRNA levels and increased LRRC37A2 exon methylation were associated with undifferentiated and poorly differentiated tumours. Moreover, LRRC37A2 gene expression and methylation levels were inversely correlated at the +45 exon CpG site. We suggest that DNA hypermethylation may contribute to reducing LRRC37A2 expression in undifferentiated and poorly differentiated GC. Therefore, our results show how some genes may be useful to stratify patients who are more likely to benefit from epigenetic therapy
Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Very few therapeutic options are currently available in this neoplasia. Epigenetic manipulation of GC cell lines is a useful tool to better understand gene expression regulatory mechanisms for clinical applications. We identified 83 candidate genes modulated by DNA methylation in GC cell lines. Among the genes identified in this analysis, we selected NRN1, TNFAIP3 and LRRC37A2 to be evaluated for gene expression by RT-qPCR and DNA methylation by bisulfite DNA next-generation sequencing in pairs of GC and adjacent non-neoplastic tissue samples. Increased expression of NRN1 and TNFAIP3 was associated with advanced tumours (P < 0.05). We showed that increased NRN1 and TNFAIP3 expression seems to be regulated by DNA demethylation in GC samples: inverse correlations between themRNA and DNA methylation levels in the promoter of NRN1 (P < 0.05) and the intron of TNFAIP3 (P < 0.05) were detected. Reduced NRN1 promoter methylation was associatedwith III/IVTNMstage tumours (P = 0.03) and the presence of Helicobacter pylori infection (P = 0.02). We showed that both reduced LRRC37A2 mRNA levels and increased LRRC37A2 exon methylation were associated with undifferentiated and poorly differentiated tumours. Moreover, LRRC37A2 gene expression and methylation levels were inversely correlated at the +45 exon CpG site. We suggest that DNA hypermethylation may contribute to reducing LRRC37A2 expression in undifferentiated and poorly differentiated GC. Therefore, our results show how some genes may be useful to stratify patients who are more likely to benefit from epigenetic therapy
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Citação
SANTOS, Leonardo Caires dos. Estudo da expressão e metilação dos genes NRN1, TNFAIP3 E LRRC37A2 no câncer gástrico. 2024. 69 f. Tese (Doutorado)- Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2024