MiR-181a regulates blood-tumor barrier permeability by targeting Kruppel-like factor 6
MiR-181a regulates blood-tumor barrier permeability by targeting Kruppel-like factor 6
复制标题
MiR-181a 通过靶向 Kruppel 样因子 6 调节血肿瘤屏障通透性
DOI：
10.1038/jcbfm.2014.152
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发表时间：
2014-11-01
影响因子：
6.3
通讯作者：
Xue, Yixue
中科院分区：
文献类型：
--
作者：
Ma, Jun;Yao, Yilong;Xue, Yixue
血肿瘤屏障（BTB）构成了一个有效的组织的紧密连接，削弱了治疗药物的输送。然而，BTB开放的方法和分子机制仍然难以捉摸。microRNAs（miRNAs）是近年来发现的一种重要的生物学调控因子，是多种生物学过程和治疗靶点的重要调控因子。在这项研究中，我们已经确定了microRNA-181 a（miR-181 a）作为开放BTB的关键miRNA。微RNA-181 a在胶质瘤内皮细胞（GECs）中表达上调，所述GECs通过将内皮细胞（ECs）与胶质瘤细胞共培养获得。过表达miR-181 a可导致BTB受损和通透性增加，同时降低闭合小带（ZO）-1、闭合蛋白和闭合蛋白-5的表达。Kruppel样因子6（KLF 6），锌指家族的转录因子，在GECs下调。机制研究将其定义为miR-181 a的直接和功能性下游靶标，其参与BTB通透性的调节以及ZO-1、occludin和claudin-5的表达。荧光素酶和染色质免疫沉淀实验表明，KLF 6可上调GECs中ZO-1、occludin和claudin-5的启动子活性，并与ZO-1、occludin和claudin-5的启动子相互作用。总的来说，我们显示了miR-181 a的过表达通过靶向KLF 6有助于BTB通透性增加的可能性，从而揭示了治疗脑胶质瘤的潜在治疗靶点。
Blood-tumor barrier (BTB) constitutes an efficient organization of tight junctions that impairs the delivery of therapeutic drugs. However, the methods and molecular mechanisms underlying the BTB opening remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of various biologic processes and therapeutic targets. In this study, we have identified microRNA-181a (miR-181a) as a critical miRNA in opening BTB. MicroRNA-181a expression was upregulated in glioma endothelial cells (GECs), which were obtained by coculturing endothelial cells (ECs) with glioma cells. Overexpression of miR-181a resulted in an impaired and permeability increased BTB, and meanwhile reduced the expression of zonula occluden (ZO)-1, occludin, and claudin-5. Kruppel-like factor 6 (KLF6), a transcription factor of the zinc-finger family, was downregulated in GECs. Mechanistic investigations defined it as a direct and functional downstream target of miR-181a, which was involved in the regulation of BTB permeability and the expression of ZO-1, occludin, and claudin-5. Furthermore, luciferase assays and chromatin immunoprecipitation assays showed that KLF6 upregulated the promoter activities and interacted with the promoters of ZO-1, occludin, and claudin-5 in GECs. Collectively, we showed the possibility that overexpression of miR-181a contributes to the increased permeability of BTB by targeting KLF6, thereby revealing potential therapeutic targets for the treatment of brain gliomas.