DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response
DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response
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DOI：
10.1007/s00204-018-2179-y
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发表时间：
2018-05-01
影响因子：
6.1
通讯作者：
Matullo, G.
中科院分区：
文献类型：
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作者：
Casalone, E.;Allione, A.;Matullo, G.
职业性和环境性石棉暴露是恶性胸膜间皮瘤(MPM)的主要决定因素，但其纤维对细胞毒性和转化的作用机制尚不完全清楚。异常的DNA甲基化是癌症中的常见事件，但特别涉及MPM致癌的表观遗传修饰需要更好地阐明。为了研究石棉诱导的DNA甲基化和基因表达的变化，我们用不同浓度的青石棉和温石棉(0.5×5.0µg/cm(2)，孵育72 h)处理Met5A间皮细胞。总体而言，在温石棉和青石棉处理中，我们观察到在石棉剂量为5微克/厘米(2)和未经处理的对照中，分别有243和302个差异甲基化的CPGS(>；=10%)。为了检验剂量-反应效应，进行了Spearman相关性检验，在两种处理中都发现了与迁移/细胞黏附过程有关的基因中显著的CPG。此外，我们发现青石棉和温石棉暴露都能显著上调CA9和SRGN的表达(log2倍变化>；1.5)，先前报道的这两种基因与更具侵袭性的MPM表型相关。然而，我们没有发现甲基化与基因表达变化之间的相关性，除了温石棉暴露后Dkk1启动子区域存在中度显著的负相关(Spearman Rho=-1，P值=0.02)。这些结果首次描述了DNA甲基化修饰和石棉暴露之间的关系。我们的发现为进一步探索和验证石棉诱导的DNA甲基化改变，从而影响MPM的致癌作用，并可能寻找新的化学预防靶点提供了基础。
Occupational and environmental asbestos exposure is the main determinant of malignant pleural mesothelioma (MPM), however, the mechanisms by which its fibres contribute to cell toxicity and transformation are not completely clear. Aberrant DNA methylation is a common event in cancer but epigenetic modifications involved specifically in MPM carcinogenesis need to be better clarified. To investigate asbestos-induced DNA methylation and gene expression changes, we treated Met5A mesothelial cells with different concentrations of crocidolite and chrysotile asbestos (0.5 divided by 5.0 mu g/cm(2), 72 h incubation). Overall, we observed 243 and 302 differentially methylated CpGs (>= 10%) between the asbestos dose at 5 mu g/cm(2) and untreated control, in chrysotile and crocidolite treatment, respectively. To examine the dose-response effect, Spearman's correlation test was performed and significant CpGs located in genes involved in migration/cell adhesion processes were identified in both treatments. Moreover, we found that both crocidolite and chrysotile exposure induced a significant up-regulation of CA9 and SRGN (log2 fold change > 1.5), previously reported as associated with a more aggressive MPM phenotype. However, we found no correlation between methylation and gene expression changes, except for a moderate significant inverse correlation at the promoter region of DKK1 (Spearman rho = -1, P value = 0.02) after chrysotile exposure. These results describe for the first time the relationship between DNA methylation modifications and asbestos exposure. Our findings provide a basis to further explore and validate asbestos-induced DNA methylation changes, that could influence MPM carcinogenesis and possibly identifying new chemopreventive target.