Department of Neurobiology, School of Life Sciences, China Medical University, 110122, Shenyang, China.
Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, 110122, Shenyang, China.
Cell Death Dis. 2019 Jul 11;10(7):536. doi: 10.1038/s41419-019-1771-2.
The existence of blood-tumor barrier (BTB) severely restricts the efficient delivery of antitumor drugs to cranial glioma tissues. Various strategies have been explored to increase BTB permeability. RNA-binding proteins and circular RNAs have recently emerged as potential regulators of endothelial cells functions. In this study, RNA-binding protein KH RNA-binding domain containing, signal transduction associated 3 (KHDRBS3) and circular RNA DENND4C (cDENND4C) were enriched in GECs. KHDRBS3 bound to cDENND4C and increased its stability. The knockdown of cDENND4C increased the permeability of BTB via downregulating the expressions of tight junction-related proteins. The miR-577 was lower expressed in GECs. The overexpressed miR-577 increased the permeability of BTB by reducing the tight junction-related protein expressions, and vice versa. Furthermore, cDENND4C acted as a molecular sponge of miR-577, which bound to miR-577 and inhibited its negative regulation of target genes ZO-1, occludin and claudin-1 to regulate BTB permeability. Single or combined treatment of KHDRBS3, cDENND4C, and miR-577 effectively promoted antitumor drug doxorubicin (DOX) across BTB to induce apoptosis of glioma cells. Collectively, the present study indicated that KHDRBS3 could regulate BTB permeability through the cDENND4C/miR-577 axis, which enhanced doxorubicin delivery across BTB. These findings may provide a novel strategy for chemotherapy of brain tumors.
血脑屏障（BTB）的存在严重限制了抗肿瘤药物向颅腔神经胶质瘤组织的有效递送。人们已经探索了各种策略来增加 BTB 的通透性。RNA 结合蛋白和环状 RNA 最近被认为是内皮细胞功能的潜在调节因子。在这项研究中，RNA 结合蛋白 KH RNA 结合域包含物、信号转导相关 3（KHDRBS3）和环状 RNA DENND4C（cDENND4C）在 GECs 中富集。KHDRBS3 与 cDENND4C 结合并增加其稳定性。cDENND4C 的敲低通过下调紧密连接相关蛋白的表达增加了 BTB 的通透性。miR-577 在 GECs 中的表达较低。过表达的 miR-577 通过减少紧密连接相关蛋白的表达来增加 BTB 的通透性，反之亦然。此外，cDENND4C 作为 miR-577 的分子海绵，与 miR-577 结合并抑制其对靶基因 ZO-1、occludin 和 claudin-1 的负调控，从而调节 BTB 通透性。KHDRBS3、cDENND4C 和 miR-577 的单独或联合治疗有效地促进了抗肿瘤药物阿霉素（DOX）穿过 BTB，诱导神经胶质瘤细胞凋亡。总之，本研究表明，KHDRBS3 可以通过 cDENND4C/miR-577 轴调节 BTB 通透性，从而增强 DOX 通过 BTB 的递送。这些发现可能为脑肿瘤的化疗提供一种新的策略。
