Long non-coding RNA MIAT regulates blood tumor barrier permeability by functioning as a competing endogenous RNA

• Published in: Cell death & disease Vol. 11; no. 10; p. 936
• Main Authors: He, Jiayuan, Xue, Yixue, Wang, Qingyuan, Zhou, Xinxin, Liu, Libo, Zhang, Tianyuan, Shang, Chao, Ma, Jun, Ma, Teng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.10.2020; Springer Nature B.V
• Subjects: 13/1; 13/89; 14/19; 3' Untranslated regions; 38/35; 38/61; 38/90; 42/44; 631/378/1341; 631/378/340; 82/80; Antibodies; Antitumor activity; Apoptosis; Astrocytes; Biochemistry; Biomedical and Life Sciences; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Cell Biology; Cell Culture; Chemotherapy; Doxorubicin; Drug delivery; Endothelial cells; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Humans; Immunology; Kinases; Life Sciences; NF-κB protein; Non-coding RNA; Permeability; Phosphorylation; RNA - genetics; RNA - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Transfection
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-03134-0

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 NF κ B-p65 (p-NF κ B-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-NF κ B-p65:NF κ B-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 NF κ B-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-NF κ B-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 NF κ B-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.