Long non-coding RNA MIAT regulates blood tumor barrier permeability by functioning as a competing endogenous RNA.
Long non-coding RNA MIAT regulates blood tumor barrier permeability by functioning as a competing endogenous RNA.
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长非编码RNA MIAT通过作为竞争性内源RNA调节血液肿瘤屏障通透性
DOI：
10.1038/s41419-020-03134-0
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发表时间：
2020-10-30
影响因子：
9
通讯作者：
Ma T
中科院分区：
文献类型：
--
作者：
He J;Xue Y;Wang Q;Zhou X;Liu L;Zhang T;Shang C;Ma J;Ma T
血肿瘤屏障（BTB）是脑内药物输送的主要障碍。因此，提高BTB的通透性对胶质瘤的治疗迫在眉睫。在这项研究中，我们证明了与血脑屏障（BBB）星形胶质细胞（ECs）共培养的内皮细胞相比，暴露于胶质瘤的BTB内皮细胞（GECs）中的MIAT、ZAK和磷酸化的NFκB-p65 （p-NFκB-p65）上调，而miR-140-3p下调。MIAT抑制miR-140-3p表达，增加ZAK表达，提高p-NFκB-p65:NFκB-p65比值，促进BTB内皮渗漏。我们目前的研究发现，miR-140-3p与ZAK 3 ‘ ’非翻译区（3 ' -UTR）互补，并且在293T细胞中，miR-140-3p抑制ZAK的荧光素酶活性。MiR-140-3p沉默通过靶向ZAK导致BTB通透性增加，而MiR-140-3p过表达在BTB的gec中具有相反的结果。ZAK的过表达诱导BTB通透性增加，这种作用与ZAK介导NFκB-p65磷酸化的能力有关。相反，ZAK沉默在BTB的gec中得到相反的结果。作为miR-140-3p的分子海绵，MIAT通过吸附miR-140-3p来减弱其对靶基因ZAK的负调控作用。通过芯片实验和荧光素酶实验，P-NFκB-p65作为转录因子负向调控tj相关蛋白的表达。单独或联合应用MIAT和miR-140-3p可有效促进抗肿瘤药物阿霉素（Dox）跨BTB诱导胶质瘤细胞凋亡。综上所述，MIAT作为miR-140-3p海绵调节其靶基因ZAK的表达，而其对NFκB-p65磷酸化的贡献与通过下调TJ相关蛋白的表达而增加BTB通透性相关，从而促进Dox在BTB中的传递。这些结果可能为胶质瘤的化疗提供新的策略和靶点。
Blood–tumor barrier (BTB) presents a major obstacle to brain drug delivery. Therefore, it is urgent to enhance BTB permeability for the treatment of glioma. In this study, we demonstrated that MIAT, ZAK, and phosphorylated NFκB-p65 (p-NFκB-p65) were upregulated, while miR-140-3p was downregulated in glioma-exposed endothelial cells (GECs) of BTB compared with those in endothelial cells cocultured with astrocytes (ECs) of blood–brain barrier (BBB). MIAT inhibited miR-140-3p expression, increased the expression of ZAK, enhanced the ratio of p-NFκB-p65:NFκB-p65, and promoted the endothelial leakage of BTB. Our current study revealed that miR-140-3p was complementary to the ZAK 3′untranslated regions (3′-UTR), and luciferase activity of ZAK was inhibited by miR-140-3p in 293T cells. MiR-140-3p silencing resulted in an increase in BTB permeability by targeting ZAK, while overexpression of miR-140-3p had the opposite results in GECs of BTB. Overexpression of ZAK induced an increase in BTB permeability, and this effect was related to ZAK’s ability to mediate phosphorylation of NFκB-p65. Conversely, ZAK silencing get opposite results in GECs of BTB. As a molecular sponge of miR-140-3p, MIAT attenuated its negative regulation of the target gene ZAK by adsorbing miR-140-3p. P-NFκB-p65 as a transcription factor negatively regulated the expression of TJ-associated proteins by means of chip assay and luciferase assay. Single or combined application of MIAT and miR-140-3p effectively promoted antitumor drug doxorubicin (Dox) across BTB to induce apoptosis of glioma cells. In summary, MIAT functioned as a miR-140-3p sponge to regulate the expression of its target gene ZAK, which contribution to phosphorylation of NFκB-p65 was associated with an increase in BTB permeability by down-regulating the expression of TJ associated proteins, thereby promoting Dox delivery across BTB. These results might provide a novel strategy and target for chemotherapy of glioma.
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长非编码RNA-MIAT促进眼睛和大脑的神经血管重塑
影响因子：
--
作者：
Jiang Q;Shan K;Qun-Wang X;Zhou RM;Yang H;Liu C;Li YJ;Yao J;Li XM;Shen Y;Cheng H;Yuan J;Zhang YY;Yan B
通讯作者：
Yan B
影响因子：
8.8
作者：
Guo, Jizhe;Shen, Shuyuan;Xue, Yixue
通讯作者：
Xue, Yixue
影响因子：
4.6
作者：
Paul A;Danley M;Saha B;Tawfik O;Paul S
通讯作者：
Paul S
混合谱系激酶 ZAK 促进癌症进展中的上皮间质转化。
影响因子：
9
作者：
Li L;Su N;Zhou T;Zheng D;Wang Z;Chen H;Yuan S;Li W
通讯作者：
Li W
影响因子：
3.7
作者：
Das S;Ghosal S;Sen R;Chakrabarti J
通讯作者：
Chakrabarti J