miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14
miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14
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miRNA-584-5p 通过抑制基质金属蛋白酶 14 的转录在人神经母细胞瘤中发挥肿瘤抑制功能
DOI：
10.1016/j.bbadis.2015.06.002
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发表时间：
2015-09-01
影响因子：
6.2
通讯作者：
Tong, Qiangsong
中科院分区：
文献类型：
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作者：
Xiang, Xuan;Mei, Hong;Tong, Qiangsong
基质金属蛋白酶14（MMP-14）是一种膜锚定的MMP，对肿瘤的发生和侵袭性至关重要，并且在神经母细胞瘤（NB）中高度表达，神经母细胞瘤是儿童最常见的颅外实体瘤。最近的证据显示内源性启动子靶向microRNA（miRNAs）在调节基因转录中的新兴作用。然而，miRNAs在MMP-14转录中的作用仍然很大程度上未知。本研究通过挖掘计算算法程序和Argonaute-染色体相互作用数据集，在MMP-14启动子内发现了一个miRNA-584- 5 p（miR-584- 5 p）的结合位点。在NB组织中，miR-584- 5 p表达不足，与MMP-14表达呈负相关，并且是患者良好预后的独立预后因素。在培养的NB细胞系中，miR-584- 5 p前体以Dicer依赖性方式减弱MMP-14的表达，导致血管内皮生长因子水平降低。此外，miR-584- 5 p抑制MMP-14的启动子活性，而miR-584- 5 p结合位点的突变则消除了这种作用。从机制上讲，miR-584- 5 p招募Argonaute 2以促进NB细胞中MMP-14启动子上zeste同源物2增强子的富集、组蛋白H3赖氨酸27三甲基化和组蛋白H3赖氨酸9二甲基化，这通过抑制miR-584- 5 p-启动子相互作用而被消除。功能获得和功能丧失研究表明，miR-584- 5 p在体外和体内抑制NB细胞的生长、侵袭、转移和血管生成。此外，MMP-14表达的恢复挽救了NB细胞的这些生物学特征的变化。综上所述，这些结果表明启动子靶向的miR-584- 5 p通过抑制MMP-14的转录在NB中发挥肿瘤抑制功能。(C)2015 Elsevier B. V.版权所有。
Matrix metalloproteinase 14 (MMP-14) is a membrane-anchored MMP crucial for tumorigenesis and aggressiveness, and is highly expressed in neuroblastoma (NB), the most common extracranial solid tumor in childhood. Recent evidence shows the emerging roles of endogenous promoter-targeting microRNAs (miRNAs) in regulating gene transcription. However, the roles of miRNAs in the transcription of MMP-14 still remain largely unknown. In this study, through mining computational algorithm program and Argonaute-chromosome interaction dataset, we identified one binding site of miRNA-584-5p (miR-584-5p) within the MMP-14 promoter. In NB tissues, miR-584-5p was under-expressed and inversely correlated with MMP-14 expression, and was an independent prognostic factor for favorable outcome of patients. miR-584-5p precursor attenuated the expression of MMP-14 in a Dicer-dependent manner, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines. In addition, miR-584-5p suppressed the promoter activity of MMP-14, and mutation of miR-584-5p binding site abolished these effects. Mechanistically, miR-584-5p recruited Argonaute 2 to facilitate the enrichment of enhancer of zeste homolog 2, histone H3 lysine 27 trimethylation, and histone H3 lysine 9 dimethylation on MMP-14 promoter in NB cells, which was abolished by repressing the miR-584-5p-promoter interaction. Gain- and loss-of-function studies demonstrated that miR-584-5p suppressed the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Moreover, restoration of MMP-14 expression rescued the NB cells from changes in these biological features. Taken together, these results indicate that promoter-targeting miR-584-5p exerts tumor suppressive functions in NB through repressing the transcription of MMP-14. (C) 2015 Elsevier B.V. All rights reserved.