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MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5

The blood-tumor barrier (BTB) hinders delivery of chemotherapeutic drugs to tumors in the brain; previous studies have shown that the BTB can be selectively opened by endothelial monocyte activating polypeptide-II (EMAP-II), but the specific mechanism involved remains elusive. In this study, we foun...

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Detalles Bibliográficos
Autores principales: Chen, Liangyu, Xue, Yixue, Zheng, Jian, Liu, Xiaobai, Liu, Jing, Chen, Jiajia, Li, Zhen, Xi, Zhuo, Teng, Hao, Wang, Ping, Liu, Libo, Liu, Yunhui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808301/
https://www.ncbi.nlm.nih.gov/pubmed/29467620
http://dx.doi.org/10.3389/fnmol.2018.00035
Descripción
Sumario:The blood-tumor barrier (BTB) hinders delivery of chemotherapeutic drugs to tumors in the brain; previous studies have shown that the BTB can be selectively opened by endothelial monocyte activating polypeptide-II (EMAP-II), but the specific mechanism involved remains elusive. In this study, we found that microRNA-429 (miR-429) expression in glioma vascular endothelial cells (GECs) was far lower than in human brain microvascular endothelial cells (ECs). miR-429 had lower expression in GECs and glioma tissues compared to ECs or normal tissues of the brain. Furthermore, miR-429 had lower expression in high grade glioma (HGG) than in low grade glioma (LGG). In in vitro BTB models, we also found that EMAP-II significantly increased BTB permeability, decreased expression of ZO-1, occludin and claudin-5 in GECs, in a time- and dose-dependent manner. EMAP-II greatly increased miR-429 expression in GECs of the BTB models in vitro. Overexpression of miR-429 in GECs significantly decreased the transepithelial electric resistance (TEER) values in BTB models, and led to enhanced horseradish peroxidase (HRP) flux. Overexpression of miR-429 in GECs significantly decreased the expression of tight junction (TJ)-associated proteins (ZO-1, occludin and claudin-5), and decreased the distribution continuity. Silencing of miR-429 in GECs increased the expression of TJ-associated proteins and the distribution continuity. The dual-luciferase reporter assay revealed that ZO-1 and occludin were target genes of miR-429, and we demonstrated that miR-429 overexpression markedly down-regulated protein expression of p70S6K, as well as its phosphorylation levels. The dual-luciferase reporter assay also showed that p70S6K was a target gene of miR-429; miR-429 overexpression down-regulated expression and phosphorylation levels of p70S6K, and also decreased phosphorylation levels of S6 and increased BTB permeability. Conversely, silencing of miR-429 increased the expression and phosphorylation levels of p70S6K, and increased phosphorylation levels of S6, while decreasing BTB permeability. In conclusion, the results indicated that EMAP-II caused an increase in miR-429 expression that directly targeted TJ-associated proteins, which were negatively regulated; on the other hand, miR-429 down-regulated the expression of TJ-associated proteins by targeting p70S6K, also negatively regulated. As a result, the BTB permeability increased.