Regulation of E3 ubiquitin ligase-1 (WWP1) by microRNA-452 inhibits cancer cell migration and invasion in prostate cancer.
Regulation of E3 ubiquitin ligase-1 (WWP1) by microRNA-452 inhibits cancer cell migration and invasion in prostate cancer.
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DOI：
10.1038/bjc.2016.95
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发表时间：
2016-05-10
影响因子：
8.8
通讯作者：
Seki N
中科院分区：
文献类型：
--
作者：
Goto Y;Kojima S;Kurozumi A;Kato M;Okato A;Matsushita R;Ichikawa T;Seki N
microRNA-224（miR-224）和microRNA-452（miR-452）紧密位于人类染色体Xq28区域。miR-224通过靶向前列腺癌（PCa）中的肿瘤蛋白D52（TPD52）发挥肿瘤抑制剂的作用。本研究旨在探讨miR-452在PCa细胞中的功能意义。使用成熟的miRNA或siRNA转染进行PCa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。通过Kaplan-Meier方法估计miR-452水平与患者总生存期之间的关联。miR-452在PCa组织中的表达显著下调。转染成熟miR-452可抑制PCa细胞的迁移和侵袭。Kaplan-Meier生存曲线显示，miR-452的低表达预示着进展为去势抵抗性PCa的持续时间较短。E3泛素蛋白连接酶1（WWP1）是miR-452的直接靶点，敲低WWP1可抑制PCa细胞的迁移和侵袭。WWP1在PCa临床标本中表达上调。miR-452-WWP1轴的调控有助于PCa细胞的迁移和侵袭，阐明该轴下游信号传导将为PCa肿瘤发生和转移的机制提供新的见解。
MicroRNA-224 (miR-224) and microRNA-452 (miR-452) are closely located on the human chromosome Xq28 region. miR-224 functions as a tumour suppressor by targeting tumour protein D52 (TPD52) in prostate cancer (PCa). Here, we aimed to investigate the functional significance of miR-452 in PCa cells. Functional studies of PCa cells were performed using transfection with mature miRNAs or siRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-452 levels and overall patient survival was estimated by the Kaplan–Meier method. Expression of miR-452 was significantly downregulated in PCa tissues. Transfection with mature miR-452 inhibited the migration and invasion of PCa cells. Kaplan–Meier survival curves showed that low expression of miR-452 predicted a short duration of progression to castration-resistant PCa. WW domain-containing E3 ubiquitin protein ligase-1 (WWP1) was a direct target of miR-452, and knockdown of WWP1 inhibited the migration and invasion of PCa cells. WWP1 was upregulated in PCa clinical specimens. Regulation of the miR-452–WWP1 axis contributed to PCa cell migration and invasion, and elucidation of downstream signalling of this axis will provide new insights into the mechanisms of PCa oncogenesis and metastasis.