Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer
Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer
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DOI：
10.1002/ijc.25461
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发表时间：
2011-03-15
影响因子：
6.4
通讯作者：
Clark, Susan J.
中科院分区：
文献类型：
--
作者：
Wiklund, Erik D.;Bramsen, Jesper B.;Clark, Susan J.
MicroRNA（miRNA）是一种小的非编码RNA，通常在癌症中失调。miR-200家族（miR-200 a、-200 b、-200 c、-141和-429）和miR-205在晚期癌症中经常沉默，并通过靶向E-钙粘蛋白、ZEB 1和ZEB 2的转录抑制因子参与上皮间质转化（EMT）和肿瘤侵袭。ZEB 1还已知在负反馈环中抑制miR-200 c-141的转录，但对miR-200家族和miR-205的转录调控知之甚少。最近，在癌症干细胞中也报道了miR-200沉默，这意味着miR-200失调是肿瘤生物学多个水平的关键事件。然而，阻止miR-200表达的因素在很大程度上仍然没有答案。在这里，我们报告了膀胱肿瘤和膀胱细胞系中miR-200和miR-205基因座的协同转录调控。通过结合miRNA表达阵列、qPCR检测和质谱DNA甲基化分析，我们发现miR-200和miR-205基因座在肌肉浸润性膀胱肿瘤和未分化膀胱细胞系中特异性沉默，并获得启动子高甲基化和抑制性染色质标记。此外，我们报告说，miR-200 c的表达与早期T1膀胱肿瘤的进展显着相关，并提出miR-200和miR-205沉默和DNA高甲基化作为可能的预后标志物在膀胱癌。此外，我们观察到中胚层转录因子TWIST 1和miR-200表达在膀胱肿瘤样品和细胞系中呈负相关。TWIST 1与miR-200和miR-205启动子直接相关，并可作为miR-200和miR-205表达的阻遏物。
MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.