Epigenetic Silencing of MicroRNA-375 Regulates PDK1 Expression in Esophageal Cancer
Epigenetic Silencing of MicroRNA-375 Regulates PDK1 Expression in Esophageal Cancer
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DOI：
10.1007/s10620-011-1711-1
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发表时间：
2011-10-01
影响因子：
3.1
通讯作者：
Li, Jiansheng
中科院分区：
文献类型：
--
作者：
Li, Xiaoli;Lin, Rui;Li, Jiansheng
microRNA（miRNAs）是一类小的（19-25个核苷酸）非编码RNA，其调节多种基因的表达，包括一些参与癌症发展的基因。最近的一些研究表明，DNA甲基化有助于肿瘤发生过程中microRNA-375（miR-375）的下调。食管癌组织中是否也存在miR-375的下调尚不清楚，为了验证miR-375在食管癌组织中也存在下调的假设，采用实时荧光定量PCR检测食管癌组织及癌旁组织中miR-375的表达水平。采用甲基化特异性PCR（MSP）检测食管癌组织中miR-375的甲基化状态，结果显示食管癌组织中miR-375启动子的高甲基化导致其表达下调。miR-375的表观遗传沉默诱导其靶点3-磷酸肌醇依赖性蛋白激酶-1（PDK 1）的上调。食管癌细胞系中miR-375表达的恢复下调了PDK 1的表达。此外，在食管癌中发现miR-375的表达与PDK 1的表达呈负相关，因此，miR-375在食管癌中频繁下调，是PDK 1的负调节因子。
MicroRNAs (miRNAs) are a class of small (19-25 nucleotides) noncoding RNAs that regulate the expressions of a wide variety of genes, including some involved in cancer development. Some recent studies show that DNA methylation contributes to down-regulation of microRNA-375 (miR-375) during tumorigenesis. Whether or not down-regulation of miR-375 also exists in esophageal cancer is unknown.Our aim was to test the hypothesis that down-regulation of miR-375 also exists in esophageal cancer.Expression of levels of miR-375 were examined using real-time PCR on paired esophageal cancer and adjacent non-cancerous tissues. The methylation status is detected by methylation specific-PCR (MSP).The results show that miR-375 is downregulated by hypermethylation of the promoter in esophageal cancer tissues. Epigenetic silencing of miR-375 induced an up-regulation of its targets, 3-phosphoinositide-dependent protein kinase-1 (PDK1). Restoration of the miR-375 expression in esophageal cancer cell lines downregulated the PDK1 expression. Furthermore, the miR-375 expression was found to be inversely correlated with PDK1 expression in esophageal cancer.Thus, miR-375 is frequently down-regulated in esophageal cancer and is a negative regulator of PDK1.