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首页> 外文期刊>Human Molecular Genetics >Metformin pharmacogenomics: a genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines
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Metformin pharmacogenomics: a genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines

机译：二甲双胍药替昔甙：一种基因组 - 基因组结合研究，以鉴定使用人淋巴母细胞系参与二甲双胍抗癌反应的遗传和表观遗传生物标志物

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摘要

Metformin is currently considered as a promising anticancer agent in addition to its anti-diabetic effect. To better individualize metformin therapy and explore novel molecular mechanisms in cancer treatment, we conducted a pharmacogenomic study using 266 lymphoblastoid cell lines (LCLs). Metformin cytotoxicity assay was performed using the MTS assay. Genome-wide association (GWA) analyses were performed in LCLs using 1.3 million SNPs, 485k DNA methylation probes, 54k mRNA expression probe sets, and metformin cytotoxicity (IC50s). Top candidate genes were functionally validated using siRNA screening, followed by MTS assay in breast cancer cell lines. Further study of one top candidate, STUB1, was performed to elucidate the mechanisms by which STUB1 might contribute to metformin action. GWA analyses in LCLs identified 198 mRNA expression probe sets, 12 SNP loci, and 5 DNA methylation loci associated with metformin IC50 with P-values?<10?4 or?<10?5. Integrated SNP/methylation loci-expression-IC50 analyses found 3 SNP loci or 5 DNA methylation loci associated with metformin IC50 through trans-regulation of expression of 11 or 26 genes with P-value?<10?4. Functional validation of top 61 candidate genes in 4 IPA networks indicated down regulation of 14 genes significantly altered metformin sensitivity in two breast cancer cell lines. Mechanistic studies revealed that the E3 ubiquitin ligase, STUB1, could influence metformin response by facilitating proteasome-mediated degradation of cyclin A. GWAS using a genomic data-enriched LCL model system, together with functional and mechanistic studies using cancer cell lines, help us to identify novel genetic and epigenetic biomarkers involved in metformin anticancer response.
机译：除了抗糖尿病效应外，二甲双胍目前被认为是有前途的抗癌剂。为了更好地互化二甲双胍治疗并探索癌症治疗的新分子机制，我们使用266个淋巴细胞细胞系（LCLS）进行了药物研究。使用MTS测定法进行二甲双胍细胞毒性测定。基因组 - 范围协会（GWA）分析在LCLS中使用130万SNPS，485K DNA甲基化探针，54K mRNA表达探针组和二甲双胍细胞毒性（IC50s）。使用siRNA筛选在功能验证顶部候选基因，然后在乳腺癌细胞系中进行MTS测定。进一步研究了一个顶部候选的stup1，以阐明Stub1可能有助于二甲双胍作用的机制。 LCLS中的GWA分析鉴定了198 mRNA表达探针组，12个SNP基因座和5个与Metformin IC50相关的5个DNA甲基化基因座，其具有p值Δ<10≤4或？<10？5。集成的SNP /甲基化基因表达-C50分析发现与二甲双胍IC50相关的3个SNP基因座或5个DNA甲基化基因座，通过对P值的11或26个基因的表达式的转变调节α<10？4。在4个IPA网络中的前61个候选基因的功能验证表明14个基因的调节显着改变了两种乳腺癌细胞中的二甲双胍敏感性。机械研究表明，通过使用基因组数据富集的LCL模型系统促进细胞蛋白A. GWA的蛋白酶体介导的细胞周期介导的细胞蛋白A介导的降解来影响二甲双胍响应。使用基因组数据富集的LCL模型系统，以及使用癌细胞系的功能和机械研究，帮助我们帮助我们鉴别参与二甲双胍抗癌反应的新型遗传和表观遗传生物标志物。

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