Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas
Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas
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FOS 介导的 miR-181b/miR-21 信号传导参与恶性胶质瘤的进展。
DOI：
10.1016/j.ejca.2013.05.010
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发表时间：
2013-09-01
影响因子：
8.4
通讯作者：
You, Yongping
中科院分区：
文献类型：
--
作者：
Tao, Tao;Wang, Yingyi;You, Yongping
最近，一组microRNAs(MiRNAs)被发现在胶质瘤中表达异常，并参与了胶质瘤的发生发展。然而，miRNA-miRNA功能网络在胶质瘤中的作用还知之甚少。在这项研究中，我们发现FBJ小鼠骨肉瘤病毒癌基因同源基因(FOS)介导的miR-181b/miR-21信号在胶质瘤进展中起关键作用。利用基因芯片和定量RT-PCR(qRT-PCR)，我们发现高级别胶质瘤FOS增加。FOS耗竭(通过FOS-shRNA)，抑制胶质瘤细胞的侵袭，促进细胞凋亡。利用基因芯片，结合Pearson相关分析，我们发现FOS与miR-21的表达呈正相关。荧光素酶报告分析表明，FOS的降低通过与miR-21启动子结合而抑制miR-21的表达。MiR-21基因的引入抑制了FOS基因敲除诱导的细胞侵袭和凋亡。此外，生物信息学和荧光素酶报告分析表明，miR-181b通过直接靶向3‘UTR内的结合位点来调控FOS的表达。FOS基因缺失3‘端非编码区的FOS表达可抑制miR-181b诱导的miR-21表达和细胞功能。免疫组织化学(IHC)和原位杂交(ISH)分析显示，miR-181b、FOS和miR-21在裸鼠移植瘤和人脑胶质瘤组织中的表达显著相关。据我们所知，首次证明miR-181b/FOS/miR-21信号在脑胶质瘤的发生发展中起重要作用，为理解转录因子介导的miRNA-miRNA功能网络在脑胶质瘤调控中的关键作用提供了重要线索。(C)2013爱思唯尔有限公司。保留所有权利。
Recently, a group of microRNAs (miRNAs) were shown to be dysregulated in gliomas, and involved in glioma development. However, the effect of miRNA-miRNA functional networks on gliomas is poorly understood. In this study, we identified that FBJ murine osteosarcoma viral oncogene homolog (FOS)-mediated miR-181b/miR-21 signalling was critical for glioma progression. Using microarrays and quantitative RT-PCR (qRT-PCR), we found increased FOS in high grade gliomas. FOS depletion (via FOS-shRNA), inhibited invasion and promoted apoptosis in glioma cells. Using microarrays, combined with Pearson correlation analysis, we found FOS positively correlated with miR-21 expression. Reduction of FOS inhibited miR-21 expression by binding to the miR-21 promoter using luciferase reporter assays. Introduction of miR-21 abrogated FOS knockdown-induced cell invasion and apoptosis. Moreover, bioinformatics and luciferase reporter assays showed that miR-181b modulated FOS expression by directly targeting the binding site within the 3'UTR. Expression of FOS with a FOS cDNA lacking 3'UTR overrided miR-181b-induced miR-21 expression and cell function. Finally, immunohistochemistry (IHC) and in situ hybridisation (ISH) analysis revealed a significant correlation in miR-181b, FOS and miR-21 expression in nude mouse tumour xenograft and human glioma tissues. To our knowledge, it is the first time to demonstrate that miR-181b/FOS/miR-21 signalling plays a critical role in the progression of gliomas, providing important clues for understanding the key roles of transcription factor mediated miRNA-miRNA functional network in the regulation of gliomas. (C) 2013 Elsevier Ltd. All rights reserved.