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首页> 外文期刊>The Journal of toxicological sciences >Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model
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Comprehensive analysis of DNA methylation and gene expression of rat liver in a 2-stage hepatocarcinogenesis model

机译：2期肝癌模型中大鼠肝脏DNA甲基化和基因表达的综合分析

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Recent studies have shown. that epigenetic alterations correlate with carcinogenesis in various tissues. Identification of these alterations might help characterize the early stages of carcinogenesis. We comprehensively analyzed DNA methylation and gene expression in livers obtained from rats exposed to nitrosodiethylamine (DEN) followed by a promoter of hepatic carcinogenesis, phenobarbital (PB). The combination of DEN and PB induced marked increases in number and area of glutathione S-transferase-placental form (GST-P)-positive foci in the liver. In the liver of rats that received 30 mg/kg of DEN, pathway analysis revealed alterations of common genes in terms of gene expression and DNA methylation, and that these alterations were related to immune responses. Hierarchical clustering analysis of the expression of common genes from public data obtained through the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system (TG-GATEs) showed that carcinogenic compounds clustered together. MBD-seq and GeneChip analysis indicated that major histocompatibility complex class Ib gene RT1-CE5, which has an important role in antigen presentation, was hypomethylated around the promoter region and specifically induced in the livers of DEN-treated rats. Further, immunohistochemical analysis indicated that the co-localization of GST-P and protein homologous to RT1-CE5 was present at the foci of some regions. These results suggest that common genes were altered in terms of both DNA methylation and expression in livers, with preneoplastic foci indicating carcinogenic potential, and that immune responses are involved in early carcinogenesis. In conclusion, the present study identified a specific profile of DNA methylation and gene expression in livers with preneoplastic foci. Early epigenetic perturbations of immune responses might correlate with the early stages of hepatocarcinogenesis.
机译：最近的研究表明。表观遗传学改变与各种组织的癌变相关。这些变化的鉴定可能有助于表征癌变的早期阶段。我们全面分析了从暴露于亚硝基二乙胺（DEN）的大鼠，然后是肝癌发生的启动子苯巴比妥（PB）的大鼠肝脏中的DNA甲基化和基因表达。 DEN和PB的组合诱导肝脏中谷胱甘肽S-转移酶-胎盘形式（GST-P）阳性灶的数量和面积显着增加。在接受30 mg / kg DEN的大鼠肝脏中，通路分析揭示了常见基因在基因表达和DNA甲基化方面的改变，并且这些改变与免疫反应有关。从通过毒物基因组计划-基因组学辅助毒性评估系统（TG-GATEs）获得的公共数据中共同基因表达的层次聚类分析表明，致癌化合物聚集在一起。 MBD-seq和GeneChip分析表明，在抗原呈递中起重要作用的主要组织相容性复合体Ib类基因RT1-CE5在启动子区域周围被甲基化，并在DEN处理的大鼠肝脏中被特异性诱导。此外，免疫组织化学分析表明在某些区域的病灶中存在与RT1-CE5同源的GST-P和蛋白质的共定位。这些结果表明，在肝脏中，DNA甲基化和表达方面的共同基因均发生了改变，肿瘤前病灶表明有潜在的致癌作用，并且免疫应答与早期致癌作用有关。总而言之，本研究确定了具有肿瘤前病灶的肝脏中DNA甲基化和基因表达的特定特征。免疫反应的早期表观遗传扰动可能与肝癌发生的早期阶段有关。

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