title: MiR-181a regulates blood-tumor barrier permeability by targeting Krüppel-like factor 6.
abstract: Blood-tumor barrier (BTB) constitutes an efficient organization of tight junctions that impairs the delivery of therapeutic drugs. However, the methods and molecular mechanisms underlying the BTB opening remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of various biologic processes and therapeutic targets. In this study, we have identified microRNA-181a (miR-181a) as a critical miRNA in opening BTB. MicroRNA-181a expression was upregulated in glioma endothelial cells (GECs), which were obtained by coculturing endothelial cells (ECs) with glioma cells. Overexpression of miR-181a resulted in an impaired and permeability increased BTB, and meanwhile reduced the expression of zonula occluden (ZO)-1, occludin, and claudin-5. Kruppel-like factor 6 (KLF6), a transcription factor of the zinc-finger family, was downregulated in GECs. Mechanistic investigations defined it as a direct and functional downstream target of miR-181a, which was involved in the regulation of BTB permeability and the expression of ZO-1, occludin, and claudin-5. Furthermore, luciferase assays and chromatin immunoprecipitation assays showed that KLF6 upregulated the promoter activities and interacted with the promoters of ZO-1, occludin, and claudin-5 in GECs. Collectively, we showed the possibility that overexpression of miR-181a contributes to the increased permeability of BTB by targeting KLF6, thereby revealing potential therapeutic targets for the treatment of brain gliomas.
authors.affiliation: 1] Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China [2] Institute of Pathology and Pathophysiology, China Medical University, Shenyang, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: 1] Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China [2] Institute of Pathology and Pathophysiology, China Medical University, Shenyang, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, People's Republic of China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1] Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China [2] Institute of Pathology and Pathophysiology, China Medical University, Shenyang, People's Republic of China.
authors.forename: Lini
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1] Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China [2] Institute of Pathology and Pathophysiology, China Medical University, Shenyang, People's Republic of China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1] Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, People's Republic of China [2] Institute of Pathology and Pathophysiology, China Medical University, Shenyang, People's Republic of China.
authors.forename: Yixue
authors.initials: Y
authors.lastname: Xue
mesh_terms: D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C107466:CLDN5 protein, human; D062507:Claudin-5; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein