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首页> 外文期刊>Cellular Signalling >MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5
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MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5

机译：MiR-18a通过RUNX1介导的ZO-1，occludin和claudin-5的下调增加了BTB的通透性

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摘要

The purposes of this study were to investigate the possible molecular mechanisms of miR-18a regulating the permeability of blood-tumor barrier (BIB) via down-regulated expression and distribution of runt-related transcription factor 1 (RUNX1). An in vitro BIB model was established with hCMEC/D3 cells and U87MG cells to obtain glioma vascular endothelial cells (GECs). The endogenous expressions of miR-18a and RUNX1 were converse in GECs. The overexpression of miR-18a significantly impaired the integrity and increased the permeability of BIB, which respectively were detected by TEER and HRP flux assays, accompanied by down-regulated mRNA and protein expressions and distributions of ZO-1, occludin and claudin-5 in GECs. Dual-luciferase reporter assay was carried out and revealed RUNX1 is a target gene of miR-18a. Meanwhile, mRNA and protein expressions and distribution of RUNX1 were downregulated by miR-18a. Most important, miR-18a and RUNX1 could reversely regulate the permeability of BIB as well as the expressions and distributions of ZO-1, occludin and claudin-5. Finally, chromatin immunoprecipitation verified that RUNX1 interacted with "TGGGGT" DNA sequence in promoter region of ZO-1, occludin and daudin-5 respectively. Taken together, our present study indicated that miR-18a increased the permeability of BIB via RUNX1 mediated down-regulation of tight junction related proteins ZO-1, occludin and claudin-5, which would attract more attention to miR-18a and RUNX1 as potential targets of drug delivery across BIB and provide novel strategies for glioma treatment (C) 2014 Elsevier Inc. All rights reserved.
机译：这项研究的目的是研究miR-18a通过下调矮子相关转录因子1（RUNX1）的表达和分布来调节血肿瘤屏障（BIB）渗透性的可能分子机制。用hCMEC / D3细胞和U87MG细胞建立了体外BIB模型，以获得神经胶质瘤血管内皮细胞（GEC）。在GEC中，miR-18a和RUNX1的内源性表达相反。 miR-18a的过表达显着削弱了BIB的完整性并增加了BIB的通透性，这分别通过TEER和HRP通量测定法检测到，同时下调了ZO-1，occludin和claudin-5的mRNA和蛋白质表达以及分布。 GEC。进行了双重荧光素酶报告基因测定，发现RUNX1是miR-18a的靶基因。同时，miR-18a下调了RUNX1的mRNA和蛋白表达及分布。最重要的是，miR-18a和RUNX1可以反向调节BIB的通透性，以及ZO-1，occludin和claudin-5的表达和分布。最后，染色质免疫沉淀证实RUNX1分别与ZO-1，occludin和daudin-5启动子区域的“ TGGGGT” DNA序列相互作用。综上所述，我们的研究表明miR-18a通过RUNX1介导的紧密连接相关蛋白ZO-1，occludin和claudin-5的下调而增加了BIB的通透性，这可能会引起人们对miR-18a和RUNX1的更多关注跨BIB的药物递送目标，并为神经胶质瘤治疗提供了新颖的策略（C）2014 Elsevier Inc.保留所有权利。

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