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MiR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of ZO-1, occludin and claudin-5.

Abstract
The purposes of this study were to investigate the possible molecular mechanisms of miR-18a regulating the permeability of blood-tumor barrier (BTB) via down-regulated expression and distribution of runt-related transcription factor 1 (RUNX1). An in vitro BTB model was established with hCMEC/D3 cells and U87MG cells to obtain glioma vascular endothelial cells (GECs). The endogenous expressions of miR-18a and RUNX1 were converse in GECs. The overexpression of miR-18a significantly impaired the integrity and increased the permeability of BTB, which respectively were detected by TEER and HRP flux assays, accompanied by down-regulated mRNA and protein expressions and distributions of ZO-1, occludin and claudin-5 in GECs. Dual-luciferase reporter assay was carried out and revealed RUNX1 is a target gene of miR-18a. Meanwhile, mRNA and protein expressions and distribution of RUNX1 were downregulated by miR-18a. Most important, miR-18a and RUNX1 could reversely regulate the permeability of BTB as well as the expressions and distributions of ZO-1, occludin and claudin-5. Finally, chromatin immunoprecipitation verified that RUNX1 interacted with "TGGGGT" DNA sequence in promoter region of ZO-1, occludin and claudin-5 respectively. Taken together, our present study indicated that miR-18a increased the permeability of BTB via RUNX1 mediated down-regulation of tight junction related proteins ZO-1, occludin and claudin-5, which would attract more attention to miR-18a and RUNX1 as potential targets of drug delivery across BTB and provide novel strategies for glioma treatment.
AuthorsYin-Sha Miao, Ying-Yu Zhao, Li-Ni Zhao, Ping Wang, Yun-Hui Liu, Jun Ma, Yi-Xue Xue
JournalCellular signalling (Cell Signal) Vol. 27 Issue 1 Pg. 156-67 (Jan 2015) ISSN: 1873-3913 [Electronic] England
PMID25452107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Claudin-5
  • Core Binding Factor Alpha 2 Subunit
  • MIRN18 microRNA, human
  • MicroRNAs
  • Occludin
  • RNA, Messenger
  • Zonula Occludens-1 Protein
Topics
  • Base Sequence
  • Brain Neoplasms (genetics, pathology)
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Claudin-5 (metabolism)
  • Core Binding Factor Alpha 2 Subunit (genetics, metabolism)
  • Down-Regulation (genetics)
  • Endothelial Cells (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Glioma (genetics, pathology)
  • Humans
  • MicroRNAs (genetics, metabolism)
  • Molecular Sequence Data
  • Occludin (metabolism)
  • Permeability
  • Promoter Regions, Genetic (genetics)
  • Protein Binding
  • RNA, Messenger (genetics, metabolism)
  • Tight Junctions (metabolism)
  • Zonula Occludens-1 Protein (metabolism)

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