Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer.
Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer.
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DOI：
10.1038/bjc.2015.195
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发表时间：
2015-07-14
影响因子：
8.8
通讯作者：
Enokida H
中科院分区：
文献类型：
--
作者：
Matsushita R;Seki N;Chiyomaru T;Inoguchi S;Ishihara T;Goto Y;Nishikawa R;Mataki H;Tatarano S;Itesako T;Nakagawa M;Enokida H
通过深度测序分析膀胱癌（BC）的microRNA（miRNA）表达特征显示，成簇的miRNA microRNA（miR）-451 a、miR-144- 3 p和miR-144- 5 p在BC组织中显著下调。我们假设这些miRNAs在BC中起肿瘤抑制因子的作用。本研究的目的是研究这些miRNA的功能作用及其对BC细胞中癌症网络的调节。使用成熟miRNA的转染进行BC细胞的功能研究。应用全基因组基因表达分析、计算机模拟分析和双荧光素酶报告基因测定来鉴定miRNA靶。确定miR-144- 5 p水平与靶基因表达之间的关联，并通过Kaplan-Meier方法估计作为靶基因表达的函数的总体患者生存期。功能获得研究显示miR-144- 5 p显著抑制BC细胞的细胞增殖。4个细胞周期相关基因（CCNE 1、CCNE 2、CDC 25 A和PKMYT 1）被鉴定为miR-144- 5 p的直接靶基因。CCNE 1和CCNE 2高表达患者的总生存率低于低表达患者（P=0.025和P=0.032）。miR-144- 5 p在BC细胞中作为肿瘤抑制因子发挥作用。CCNE 1和CCNE 2受miR-144- 5 p直接调控，可能是BC患者生存的良好预后标志物。
Analysis of a microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that clustered miRNAs microRNA (miR)-451a, miR-144-3p, and miR-144-5p were significantly downregulated in BC tissues. We hypothesised that these miRNAs function as tumour suppressors in BC. The aim of this study was to investigate the functional roles of these miRNAs and their modulation of cancer networks in BC cells. The functional studies of BC cells were performed using transfection of mature miRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-144-5p levels and expression of the target genes was determined, and overall patient survival as a function of target gene expression was estimated by the Kaplan–Meier method. Gain-of-function studies showed that miR-144-5p significantly inhibited cell proliferation by BC cells. Four cell cycle-related genes (CCNE1, CCNE2, CDC25A, and PKMYT1) were identified as direct targets of miR-144-5p. The patients with high CCNE1 or CCNE2 expression had lower overall survival probabilities than those with low expression (P=0.025 and P=0.032). miR-144-5p functions as tumour suppressor in BC cells. CCNE1 and CCNE2 were directly regulated by miR-144-5p and might be good prognostic markers for survival of BC patients.