Global hypomethylation of genomic DNA in cancer-associated myofibroblasts.
Global hypomethylation of genomic DNA in cancer-associated myofibroblasts.
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DOI：
10.1158/0008-5472.can-08-1319
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发表时间：
2008-12-01
期刊：
影响因子：
11.2
通讯作者：
Tycko B
中科院分区：
文献类型：
--
作者：
Jiang L;Gonda TA;Gamble MV;Salas M;Seshan V;Tu S;Twaddell WS;Hegyi P;Lazar G;Steele I;Varro A;Wang TC;Tycko B
甲基化的整体丧失长期以来被认为是人类癌中恶性上皮成分的特征。在这里，我们展示了癌症相关基质肌成纤维细胞中相同类型的表观遗传学改变的证据。我们使用甲基化敏感的SNP阵列分析（MSNP）来分析从人胃癌中分离的间质肌成纤维细胞的早期传代培养物中的DNA甲基化。MSNP数据表明这些细胞中甲基化的广泛丢失，具有罕见的甲基化的局灶性增益，通过亚硫酸氢盐测序和甲基化敏感的胞嘧啶掺入测定独立验证的结论。在一系列胃切除术标本中使用抗甲基胞嘧啶（抗甲基-C）的免疫组织化学（IHC）显示，肠型和弥漫性癌的恶性上皮细胞和α平滑肌肌动蛋白（ASMA）阳性基质肌成纤维细胞的细胞核中甲基化频繁丢失。我们证实了这一现象，并建立了其发病阶段的非侵入性发育异常病变的抗甲基-C在转基因小鼠模型的多阶段胃癌。这些发现表明癌细胞及其伴随的反应性基质细胞中表观遗传改变的相似的一般类别，并增加了正常和癌症相关肌成纤维细胞之间生物学差异的积累证据。
Global loss of methylation has long been recognized as a feature of the malignant epithelial component in human carcinomas. Here we show evidence for this same type of epigenetic alteration in cancer-associated stromal myofibroblasts. We used methylation-sensitive SNP array analysis (MSNP) to profile DNA methylation in early passage cultures of stromal myofibroblasts isolated from human gastric cancers. The MSNP data indicated widespread loss of methylation in these cells, with rare focal gains of methylation, conclusions that were independently validated by bisulfite sequencing and by a methylation-sensitive cytosine incorporation assay. Immunohistochemistry (IHC) using anti-methylcytosine (anti-methyl-C) in a series of gastrectomy specimens showed frequent loss of methylation in nuclei of both the malignant epithelial cells and the alpha smooth muscle actin (ASMA)-positive stromal myofibroblasts of both intestinal type and diffuse carcinomas. We confirmed this phenomenon and established its onset at the stage of non-invasive dysplastic lesions by IHC for anti-methyl-C in a transgenic mouse model of multi-stage gastric carcinogenesis. These findings indicate similar general classes of epigenetic alterations in carcinoma cells and their accompanying reactive stromal cells and add to accumulating evidence for biological differences between normal and cancer-associated myofibroblasts.