Overexpression of miR-18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood-tumor barrier via Krüppel-like factor 4-mediated downregulation of zonula occluden-1, claudin-5, and occludin

• Published in: Journal of neuroscience research Vol. 93; no. 12; pp. 1891 - 1902
• Main Authors: Zhao, Ying-Yu, Zhao, Li-Ni, Wang, Ping, Miao, Yin-Sha, Liu, Yun-Hui, Wang, Zhen-Hua, Ma, Jun, Li, Zhen, Li, Zhi-Qing, Xue, Yi-Xue
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2015; Wiley Subscription Services, Inc
• Subjects: AB_10375873; AB_10835246; AB_10836283; AB_10836645; AB_1310389; AB_398095; Blood-Brain Barrier - cytology; blood-tumor barrier; Capillary Permeability - physiology; Cell Line, Transformed; Chromatin Immunoprecipitation; Claudin-5 - metabolism; Down-Regulation - physiology; Epithelial Cells - metabolism; Glioma - pathology; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Horseradish Peroxidase - metabolism; Humans; KLF4; Kruppel-Like Transcription Factors - metabolism; MEF2 Transcription Factors - metabolism; MEF2D; MicroRNAs - genetics; MicroRNAs - metabolism; miR-18a; nif-0000-02738; Occludin - metabolism; OMICS_00420; Permeability; RNA, Messenger - metabolism; tight junction-related proteins; Transfection; Zonula Occludens Proteins - genetics; Zonula Occludens Proteins - metabolism; Zonula Occludens-1 Protein - metabolism; nif-0000-02738; tight junction-related proteins; KLF4; AB_10836283; AB_1310389; miR-18a; AB_10375873; AB_10835246; OMICS_00420; AB_10836645; AB_398095; blood-tumor barrier; MEF2D
• ISSN: 0360-4012; 1097-4547
• DOI: 10.1002/jnr.23628

miR‐18a represses angiogenesis and tumor evasion by weakening vascular endothelial growth factor and transforming growth factor‐β signaling to prolong the survival of glioma patients, although it is thought to be an oncogene. This study investigates the potential effects of miR‐18a on the permeability of the blood–tumor barrier (BTB) and its possible molecular mechanisms. An in vitro BTB model was successfully established. The endogenous expression of miR‐18a in glioma vascular endothelial cells (GECs) was significantly lower than that in normal vascular ECs, and the overexpression of miR‐18a significantly increased the permeability of the BTB as well as downregulating the mRNA and protein expressions of tight junction‐related proteins zonula occluden‐1 (ZO‐1), claudin‐5, and occludin in GECs. Dual luciferase reporter assays revealed that miR‐18a bound to the 3′‐untranslated region (3′UTR) of myocyte enhancer factor 2D (MEF2D). The overexpression of both miR‐18a and MEF2D with the 3′UTR significantly weakened the effect caused by miR‐18a of decreasing the mRNA and protein expressions of ZO‐1, claudin‐5 and occludin and of increasing the permeability of the BTB. Chromatin immunoprecipitation showed that MEF2D could directly bind to KLF4 promoter. This study shows that miR‐18a targets and negatively regulates MEF2D, which further regulates tight junction‐related proteins ZO‐1, claudin‐5, and occludin through transactivation of KLF4 and, finally, changes the permeability of the BTB. MiR‐18a should garner growing attention because it might serve as a potential target in opening the BTB and providing a new strategy for the treatment of gliomas. © 2015 Wiley Periodicals, Inc. MiR‐18a targets and negatively regulates MEF2D, which further regulates tight junction‐related proteins ZO‐1, claudin‐5, and occludin through transactivation of KLF4 and finally results in opening the BTB. → expresses activation; ⊣ expresses inhibition.