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

ABSTRACT: 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?B-p65 (p-NF?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?B-p65:NF?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?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?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?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.

SUBMITTER: He J

PROVIDER: S-EPMC7603350 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

He Jiayuan J Xue Yixue Y Wang Qingyuan Q Zhou Xinxin X Liu Libo L Zhang Tianyuan T Shang Chao C Ma Jun J Ma Teng T

Cell death & disease 20201030 10

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 ...[more]

PMID: 33127881

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Project description:Schizophrenia (SCZ) is a serious psychiatric condition with a 1% lifetime risk. SCZ is one of the top ten global causes of disabilities. Despite numerous attempts to understand the function of genetic factors in SCZ development, genetic components in SCZ pathophysiology remain unknown. The competing endogenous RNA (ceRNA) network has been demonstrated to be involved in the development of many kinds of diseases. The ceRNA hypothesis states that cross-talks between coding and non-coding RNAs, including long non-coding RNAs (lncRNAs), via miRNA complementary sequences known as miRNA response elements, creates a large regulatory network across the transcriptome. In the present study, we developed a lncRNA-related ceRNA network to elucidate molecular regulatory mechanisms involved in SCZ. Microarray datasets associated with brain regions (GSE53987) and lymphoblasts (LBs) derived from peripheral blood (sample set B from GSE73129) of SCZ patients and control subjects containing information about both mRNAs and lncRNAs were downloaded from the Gene Expression Omnibus database. The GSE53987 comprised 48 brain samples taken from SCZ patients (15 HPC: hippocampus, 15 BA46: Brodmann area 46, 18 STR: striatum) and 55 brain samples taken from control subjects (18 HPC, 19 BA46, 18 STR). The sample set B of GSE73129 comprised 30 LB samples (15 patients with SCZ and 15 controls). Differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) were identified using the limma package of the R software. Using DIANA-LncBase, Human MicroRNA Disease Database (HMDD), and miRTarBase, the lncRNA- associated ceRNA network was generated. Pathway enrichment of DEmRNAs was performed using the Enrichr tool. We developed a protein-protein interaction network of DEmRNAs and identified the top five hub genes by the use of STRING and Cytoscape, respectively. Eventually, the hub genes, DElncRNAs, and predictive miRNAs were chosen to reconstruct the subceRNA networks. Our bioinformatics analysis showed that twelve key DEmRNAs, including BDNF, VEGFA, FGF2, FOS, CD44, SOX2, NRAS, SPARC, ZFP36, FGG, ELAVL1, and STARD13, participate in the ceRNA network in SCZ. We also identified DLX6-AS1, NEAT1, MINCR, LINC01094, DLGAP1-AS1, BABAM2-AS1, PAX8-AS1, ZFHX4-AS1, XIST, and MALAT1 as key DElncRNAs regulating the genes mentioned above. Furthermore, expression of 15 DEmRNAs (e.g., ADM and HLA-DRB1) and one DElncRNA (XIST) were changed in both the brain and LB, suggesting that they could be regarded as candidates for future biomarker studies. The study indicated that ceRNAs could be research candidates for investigating SCZ molecular pathways.

Dataset Information

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

Publications

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

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