EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis.
EIF4A3-induced circular RNA MMP9 (circMMP9) acts as a sponge of miR-124 and promotes glioblastoma multiforme cell tumorigenesis.
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EIF4A3 诱导的环状 RNA MMP9 (circMMP9) 作为 miR-124 的海绵，促进多形性胶质母细胞瘤细胞肿瘤发生。
DOI：
10.1186/s12943-018-0911-0
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发表时间：
2018-11-23
期刊：
影响因子：
37.3
通讯作者：
Liang H
中科院分区：
文献类型：
--
作者：
Wang R;Zhang S;Chen X;Li N;Li J;Jia R;Pan Y;Liang H
环状RNA(CircRNAs)在多种癌症的发生和发展中起着关键作用。然而，环状RNA网络对多形性胶质母细胞瘤(GBM)的影响知之甚少。采用基因芯片技术筛选GBM中CircRNA的表达。用实时定量聚合酶链式反应检测CircMMP9的表达。将CircMMP9过表达载体或siRNA导入GBM细胞，观察细胞的增殖、迁移、侵袭以及裸鼠体内的致瘤性，以检测CircMMP9对GBM的影响。通过生物素偶联miRNA捕获、荧光原位杂交和荧光素酶报告基因检测，证实了CircMMP9与miR-124之间的关系。在本研究中，我们筛选了差异表达的CircRNAs，并鉴定了在GBM中的CircMMP9。我们发现，CircMMP9作为癌基因在GBM中表达上调，并促进GBM细胞的增殖、迁移和侵袭能力。接下来，我们验证了CircMMP9作为直接靶向miR-124的海绵；CircMMP9通过靶向miR-124促进了GBM细胞的增殖、迁移和侵袭。此外，我们还发现细胞周期蛋白依赖的蛋白4(CDK4)和极光蛋白A(AURKA)参与了CircMMP9/miR-124轴诱导的基底膜肿瘤的发生。最后，我们发现真核细胞起始因子4A3(EIF4A3)与MMP9的mRNA转录本结合，可诱导GBM中CircMMP9的环化，增加CircMMP9的表达。我们的研究结果表明，eIF4A3通过调控miR-124信号转导通路，在GBM细胞的增殖、侵袭和转移中起重要作用，为GBM的治疗提供了重要的潜在治疗靶点。本文的在线版本(10.1186/s12943-0180911-0)包含补充材料，可供授权用户使用。
Circular RNAs (circRNAs) have been found to play critical roles in the development and progression of various cancers. However, little is known about the effects of the circular RNA network on glioblastoma multiforme (GBM). A microarray was used to screen circRNA expression in GBM. Quantitative real-time PCR was used to detect the expression of circMMP9. GBM cells were transfected with a circMMP9 overexpression vector or siRNA, and cell proliferation, migration and invasion, as well as tumorigenesis in nude mice, were assessed to examine the effect of circMMP9 in GBM. Biotin-coupled miRNA capture, fluorescence in situ hybridization and luciferase reporter assays were conducted to confirm the relationship between circMMP9 and miR-124. In this study, we screened differentially expressed circRNAs and identified circMMP9 in GBM. We found that circMMP9 acted as an oncogene, was upregulated in GBM and promoted the proliferation, migration and invasion abilities of GBM cells. Next, we verified that circMMP9 served as a sponge that directly targeted miR-124; circMMP9 accelerated GBM cell proliferation, migration and invasion by targeting miR-124. Furthermore, we found that cyclin-dependent kinase 4 (CDK4) and aurora kinase A (AURKA) were involved in circMMP9/miR-124 axis-induced GBM tumorigenesis. Finally, we found that eukaryotic initiation factor 4A3 (eIF4A3), which binds to the MMP9 mRNA transcript, induced circMMP9 cyclization and increased circMMP9 expression in GBM. Our findings indicate that eIF4A3-induced circMMP9 is an important underlying mechanism in GBM cell proliferation, invasion and metastasis through modulation of the miR-124 signaling pathway, which could provide pivotal potential therapeutic targets for the treatment of GBM. The online version of this article (10.1186/s12943-018-0911-0) contains supplementary material, which is available to authorized users.
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作者：
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通讯作者：
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DOI：
10.1093/jnci/djx166
发表时间：
2018-03-01
期刊：
Journal of the National Cancer Institute
影响因子：
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作者：
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