DNA methylation changes in a human cell model of breast cancer progression.
DNA methylation changes in a human cell model of breast cancer progression.
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DOI：
10.1016/j.mrfmmm.2010.02.007
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发表时间：
2010-06-01
影响因子：
2.3
通讯作者：
Russo, Jose
中科院分区：
文献类型：
--
作者：
Fernandez, Sandra V.;Snider, Kara E.;Wu, Yue-Zhong;Russo, Irma H.;Plass, Christoph;Russo, Jose
DNA超甲基化导致的基因表观遗传失活在肿瘤发生中起着重要作用。采用体外人乳腺上皮细胞转化模型，研究雌二醇在肿瘤形成过程中诱导的表观遗传学变化。肿瘤起始和进展的不同阶段在该模型中表示为MCF-10 F，正常阶段; trMCF细胞，转化阶段; bsMCF细胞，侵袭阶段和caMCF细胞，肿瘤阶段。通过限制性标记基因组扫描（RLGS）进行的全局甲基化研究显示，在侵袭性和肿瘤阶段，DNA甲基化增加。表达研究表明，NRG 1（神经调节蛋白1），CSS3（硫酸软骨素合成酶3）和SNIP（SNAP-25相互作用蛋白）在侵袭性和肿瘤细胞中下调。与亲本细胞MCF-10 F相比，转化的细胞显示STXBP 6（淀粉溶素）的低表达。用单独的去甲基化剂5-aza-dC或与组蛋白去乙酰化酶抑制剂阿司他汀组合处理这些细胞增加了NRG 1、STXBP 6、CSS3和SNIP的表达，证实DNA甲基化在调节这些基因的表达中起重要作用。NRG 1外显子1有一个区域位于−136至+79（考虑+1，翻译起始位点）之间，富含CpG位点，通过甲基化特异性PCR（MSP）分析。在该模型中，NRG 1外显子1显示出与肿瘤过程进展相关的甲基化模式的进行性变化; NRG 1外显子1在MCF-10 F和trMCF细胞中未甲基化，在侵袭性（bsMCF）和肿瘤（caMCF）阶段变得高甲基化。对人类乳腺组织样本的研究表明，NRG 1外显子1在17例浸润性癌中有14例（82.4%）发生部分甲基化，而在正常组织中未发生甲基化（10例正常乳腺组织样本中有8例）。此外，NRG 1外显子1部分甲基化的14例（64.3%），形态正常的组织样本中的9个浸润性癌。
Epigenetic inactivation of genes by DNA hypermethylation plays an important role in carcinogenesis. An in vitro model of human breast epithelial cell transformation was used to study epigenetic changes induced by estradiol during the neoplastic process. Different stages of tumor initiation and progression are represented in this model being MCF-10F the normal stage; trMCF cells, the transformed stage; bsMCF cells, the invasive stage and, caMCF cells, the tumor stage. Global methylation studies by restriction landmark genomic scanning (RLGS) showed an increased DNA-methylation during the in the invasive and tumor stages. Expression studies showed that NRG1 (neuregulin 1), CSS3 (chondroitin sulfate synthase 3) and SNIP (SNAP-25-interacting protein) were downregulated in the invasive and tumor cells. The transformed cells showed low expression of STXBP6 (amysin) compared to the parental cells MCF-10F. The treatment of these cells with the demethylating agent 5-aza-dC alone or in combination with the histone deacetylase inhibitor trichostatin increased the expression of NRG1, STXBP6, CSS3 and SNIP confirming that DNA methylation plays an important role in the regulation of the expression of these genes. The NRG1 exon 1 has a region located between −136 to +79 (considering +1, the translational initiation site) rich in CpG sites that was analyzed by methylation specific PCR (MSP). NRG1 exon 1 showed progressive changes in the methylation pattern associated with the progression of the neoplastic process in this model; NRG1 exon 1 was unmethylated in MCF-10F and trMCF cells, becoming hypermethylated in the invasive (bsMCF) and tumor (caMCF) stages. Studies of human breast tissue samples showed that NRG1 exon 1 was partially methylated in 14 out of 17 (82.4%) invasive carcinomas although it was unmethylated in normal tissues (8 out of 10 normal breast tissue samples). Furthermore, NRG1 exon 1 was partially methylated in 9 out of 14 (64.3%) morphologically normal tissue samples adjacent to invasive carcinomas.
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DOI：
10.1073/pnas.93.18.9821
发表时间：
1996-09-03
影响因子：
11.1
作者：
Herman, JG;Graff, JR;Baylin, SB
通讯作者：
Baylin, SB
影响因子：
1.5
作者：
Fernandez SV;Russo J
通讯作者：
Russo J
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
5.6
作者：
Offterdinger, M;Schneider, SM;Grunt, TW
通讯作者：
Grunt, TW
影响因子：
11.2
作者：
Huang, HE;Chin, SF;Edwards, PAW
通讯作者：
Edwards, PAW