A feed-forward regulatory loop between androgen receptor and PlncRNA-1 promotes prostate cancer progression
A feed-forward regulatory loop between androgen receptor and PlncRNA-1 promotes prostate cancer progression
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DOI：
10.1016/j.canlet.2016.01.033
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发表时间：
2016-04-28
期刊：
影响因子：
9.7
通讯作者：
Sun, Yinghao
中科院分区：
文献类型：
--
作者：
Fang, Ziyu;Xu, Chen;Sun, Yinghao
我们先前曾报道，在前列腺癌(Pca)中上调的PlncRNA-1是一种长的非编码RNA，它影响前列腺癌细胞的增殖和凋亡。然而，这些效应背后的分子机制在很大程度上仍不清楚。在这项研究中，我们证明了雄激素受体(AR)促进其表达的长非编码RNA PlncRNA-1在PCa细胞中保护AR免受microRNA介导的抑制。PlncRNA-1基因下调导致一系列针对AR的microRNAs表达上调，其中miR-34c和miR-297在转录后水平调节AR和PlncRNA-1的表达。功能分析表明，miR-34c和miR-297过表达下调了AR的表达，并抑制了下游AR靶点的表达，而PlncRNA-1的过表达挽救了这些作用。在小鼠异种移植模型、PCa组织(16个配对样本)和血液样本(35个活检阴性和37个活检阳性)中也评估了PlncRNA-1与肿瘤进展的相关性。综上所述，本研究中产生的数据表明，PlncRNA-1海绵AR靶向microRNAs，以保护AR免受microRNA介导的下调，并且这些事件在PCa的发展过程中形成了一个调节前馈环。这些发现表明，PlncRNA-1可能作为一种新的PCa生物标志物，并且PlncRNA-1可能值得进一步研究，以确定其作为PCa治疗靶点的潜在作用。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
We previously reported that PlncRNA-1, a long non-coding RNA that is up-regulated in prostate cancer (PCa), affects the proliferation and apoptosis of PCa cells. However, the molecular mechanisms underlying these effects remain largely unknown. In this study, we demonstrated that long non-coding RNA PlncRNA-1, whose expression is promoted by Androgen Receptor (AR), protects AR from microRNA-mediated suppression in PCa cells. PlncRNA-1 knockdown resulted in the up-regulation of a series of AR targeting microRNAs, among which miR-34c and miR-297 were found to regulate both AR and PlncRNA-1 expression at the post-transcriptional level. Functional analysis revealed that miR-34c and miR-297 overexpression down-regulated AR expression and inhibited the expression of downstream AR targets and that PlncRNA-1 overexpression rescued these effects. The association of PlncRNA-1 with tumor progression was also evaluated in mouse xenograft models, PCa tissues (16 paired samples), and blood samples (35 biopsy-negative and 37 biopsy-positive). Together, the data generated in this study indicate that PlncRNA-1 sponges AR-targeting microRNAs to protect AR from microRNA-mediated down-regulation and that these events form a regulatory feed-forward loop in the development of PCa. These findings suggest that PlncRNA-1 might potentially serve as a novel biomarker in PCa and that PlncRNA-1 might warrant further investigation to determine its potential role as a promising therapeutic target in PCa. (C) 2016 Elsevier Ireland Ltd. All rights reserved.