The impact of DNA demethylation on the upregulation of the NRN1 and TNFAIP3 genes associated with advanced gastric cancer.

Autor: Wisnieski F; Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil. f.wisnieski@unifesp.br.; Disciplina de Gastroenterologia, Departamento de Medicina, Universidade Federal de São Paulo, Rua Loefgreen, 1726, São Paulo, São Paulo, 04040002, Brazil. f.wisnieski@unifesp.br., Santos LC; Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil., Calcagno DQ; Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil., Geraldis JC; Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil., Gigek CO; Departamento de Patologia, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil., Anauate AC; Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil., Chen ES; Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil., Rasmussen LT; Disciplina de Genética, Hemocentro da Faculdade de Medicina de Marília, Rua Lourival Freire, 240, Marília, São Paulo, 17519-050, Brazil., Payão SLM; Disciplina de Genética, Hemocentro da Faculdade de Medicina de Marília, Rua Lourival Freire, 240, Marília, São Paulo, 17519-050, Brazil., Artigiani R; Departamento de Patologia, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil., Demachki S; Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil., Assumpção PP; Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil., Lourenço LG; Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo, R. Napoleão de Barros, 715, São Paulo, 04024002, Brazil., Arasaki CH; Disciplina de Gastroenterologia Cirúrgica, Departamento de Cirurgia, Universidade Federal de São Paulo, R. Napoleão de Barros, 715, São Paulo, 04024002, Brazil., Pabinger S; Austrian Institute of Technology, Center for Health & Bioresources, Molecular Diagnostics, Giefinggasse 4, 1210, Vienna, Austria., Krainer J; Austrian Institute of Technology, Center for Health & Bioresources, Molecular Diagnostics, Giefinggasse 4, 1210, Vienna, Austria., Leal MF; Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil.; Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil., Burbano RR; Programa de Pós-graduação em Oncologia e Ciências Médicas, Universidade Federal do Pará, Rua dos Mundurucus, 4487, Belém, Pará, 66073-000, Brazil.; Laboratório de Biologia Molecular, Hospital Ophir Loyola, Avenida Governador Magalhães, 992, Belém, 66063-240, Brazil., Arruda Cardoso Smith M; Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil. macsmith@unifesp.br.
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2020 May; Vol. 98 (5), pp. 707-717. Date of Electronic Publication: 2020 Apr 13.
DOI: 10.1007/s00109-020-01902-1
Abstrakt: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Very few therapeutic options are currently available in this neoplasia. The use of 5-Aza-2'-deoxycytidine (5-AZAdC) was approved for the treatment of myelodysplastic syndromes, and this drug can treat solid tumours at low doses. Epigenetic manipulation of GC cell lines is a useful tool to better understand gene expression regulatory mechanisms for clinical applications. Therefore, we compared the gene expression profile of 5-AZAdC-treated and untreated GC cell lines by a microarray assay. Among the genes identified in this analysis, we selected NRN1 and TNFAIP3 to be evaluated for gene expression by RT-qPCR and DNA methylation by bisulfite DNA next-generation sequencing in 43 and 52 pairs of GC and adjacent non-neoplastic tissue samples, respectively. We identified 83 candidate genes modulated by DNA methylation in GC cell lines. 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 the mRNA 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 associated with III/IV TNM stage tumours (P = 0.03) and the presence of Helicobacter pylori infection (P = 0.02). The identification of demethylated activated genes in GC may be useful in clinical practice, stratifying patients who are less likely to benefit from 5-AZAdC-based therapies. KEY MESSAGES: Higher expression of NRN1 and TNFAIP3 is associated with advanced gastric cancer (GC). NRN1 promoter hypomethylation contributes to gene upregulation in advanced GC. TNFAIP3 intronic-specific CpG site demethylation contributes to gene upregulation in GC. These findings may be useful to stratify GC patients who are less likely to benefit from DNA demethylating-based therapies.
Databáze: MEDLINE
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