The Landscape of microRNA Targeting in Prostate Cancer Defined by AGO-PAR-CLIP.
The Landscape of microRNA Targeting in Prostate Cancer Defined by AGO-PAR-CLIP.
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DOI：
10.1016/j.neo.2016.04.008
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
McGuire SE
中科院分区：
文献类型：
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作者：
Hamilton MP;Rajapakshe KI;Bader DA;Cerne JZ;Smith EA;Coarfa C;Hartig SM;McGuire SE
前列腺癌(PCa)中的microRNA(MiRNA)失调控有助于前列腺癌的启动和转移。为了全面确定在通常研究的PCa模型中与癌症相关的miRNA靶向和功能的变化，我们在一组模拟PCa进展不同阶段的PCa细胞系中进行了可光激活的核糖核苷增强的交联型免疫沉淀。使用这个完整的miRNA靶标目录，我们分析了已知的PCA驱动因素上的miRNA靶向，并研究了miRNAs的组织特异性和阶段特异性途径靶向。我们发现雄激素受体是最常见的靶向PCa癌基因，而miR-148A靶向最多的已知PCa驱动因素。从全球来看，miRNA靶向的组织特异性和阶段特异性变化是由对活跃的致癌途径的动态平衡反应驱动的。我们的发现表明，即使在晚期PCa中，miRNA池也适用于调节癌症基因组中的持续变化，以平衡致癌分子的变化。这些发现很重要，因为它们是第一次对PCa中miRNA的变化进行全球表征，并展示了miRNA靶谱如何对分期的肿瘤发生做出反应。
MicroRNA (miRNA) deregulation in prostate cancer (PCa) contributes to PCa initiation and metastatic progression. To comprehensively define the cancer-associated changes in miRNA targeting and function in commonly studied models of PCa, we performed photoactivatable ribonucleoside-enhanced cross-linking immunoprecipitation of the Argonaute protein in a panel of PCa cell lines modeling different stages of PCa progression. Using this comprehensive catalogue of miRNA targets, we analyzed miRNA targeting on known drivers of PCa and examined tissue-specific and stage-specific pathway targeting by miRNAs. We found that androgen receptor is the most frequently targeted PCa oncogene and that miR-148a targets the largest number of known PCa drivers. Globally, tissue-specific and stage-specific changes in miRNA targeting are driven by homeostatic response to active oncogenic pathways. Our findings indicate that, even in advanced PCa, the miRNA pool adapts to regulate continuing alterations in the cancer genome to balance oncogenic molecular changes. These findings are important because they are the first to globally characterize miRNA changes in PCa and demonstrate how the miRNA target spectrum responds to staged tumorigenesis.