Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer
Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer
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DOI：
10.1038/onc.2012.300
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发表时间：
2013-06-06
期刊：
影响因子：
8
通讯作者：
Clark, S. J.
中科院分区：
文献类型：
--
作者：
Hulf, T.;Sibbritt, T.;Clark, S. J.
microRNA（miRNA）表达的失调在癌症发生中具有关键作用。在这里，我们发现在前列腺癌中，miRNA-205（miR-205）转录通常受到抑制，MIR-205位点高度甲基化。L0 C642587，功能未知的MIR-205宿主基因，也一致失活。我们发现，miR-205靶向介体1（MED 1，也称为TRAP 220和PPARBP）在正常前列腺细胞中进行转录沉默，导致MED 1 mRNA水平降低，以及总磷酸化MED 1蛋白和活性磷酸化MED 1蛋白。miR-205在前列腺癌细胞中的过表达负面影响细胞活力，与肿瘤抑制功能一致。我们发现，与匹配的正常前列腺（n = 7）相比，原发性肿瘤样本（n = 14）中MIR-205基因座的超甲基化与miR-205表达的降低和MED 1表达的增加密切相关。扩展的患者队列（肿瘤n = 149，匹配的正常n = 30）也显示与正常相比，肿瘤中MIR-205 DNA甲基化显著，MIR-205高甲基化与生化复发显著相关（风险比= 2.005，95%置信区间（1.109，3.625），P = 0.02）。总之，这些结果表明，miR-205是一种靶向MED 1的表观遗传学调节的肿瘤抑制因子，可能为前列腺癌管理提供潜在的生物标志物。
Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n = 14), when compared with matched normal prostate (n = 7). An expanded patient cohort (tumor n = 149, matched normal n = 30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio = 2.005, 95% confidence interval (1.109, 3.625), P = 0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management.