title: Long non-coding RNA NEAT1 regulates permeability of the blood-tumor barrier via miR-181d-5p-mediated expression changes in ZO-1, occludin, and claudin-5.
abstract: The blood-tumor barrier (BTB) constitutes an efficient organization of tight junctions that limits the delivery of chemotherapeutic drugs to brain tumor tissues and impacts the treatment of glioma. Long non-coding RNAs (lncRNAs) are non-protein coding RNAs regulating gene expression, some lncRNAs play a crucial role in BTB permeability. However, the function of lncRNAs in BTB permeability is still largely unclear. Here, we have identified lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), was remarkably up-regulated in glioma endothelial cells (GECs) obtained from an in vitro BTB model. Knockdown of NEAT1 impaired the integrity and increased the permeability of the BTB, accompanied by downregulation of expression of the tight junction proteins ZO-1, occludin and claudin-5 in GECs. Both bioinformatics data and results of luciferase reporter assays demonstrated that NEAT1 influenced BTB permeability by binding to miR-181d-5p. Knockdown of NEAT1 also down-regulated the expression of sex determining region Y-box protein 5 (SOX5), which was defined as a direct and functional downstream target of miR-181d-5p. SOX5 interacts with the promoter region of ZO-1, occludin and claudin-5 in GECs. In conclusion, knockdown of NEAT1 increased BTB permeability by binding to miR-181d-5p and then reducing tight junction protein expression by targeting SOX5. These results suggest an important role for NEAT1 in regulating BTB permeability and provide an additional strategy for treating glioma.
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, People's Republic of China.
authors.forename: Junqing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China; Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang 110004, People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China; Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang 110004, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China; Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang 110004, People's Republic of China.
authors.forename: Xiaobai
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China; Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang 110004, People's Republic of China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, 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 110004, People's Republic of China; Liaoning Research Center for Translational Medicine in Nervous System Disease, Shenyang 110004, People's Republic of China.
authors.forename: Zhongyou
authors.initials: Z
authors.lastname: Que
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, People's Republic of China.
authors.forename: Yana
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tao
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, People's Republic of China. Electronic address: xueyixue888@163.com.
authors.forename: Yixue
authors.initials: Y
authors.lastname: Xue
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D062507:Claudin-5 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D062793:Occludin / Q000096:biosynthesis / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism; D062725:Tight Junction Proteins / Q000096:biosynthesis*; D062826:Zonula Occludens-1 Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: C107466:CLDN5 protein, human; D062507:Claudin-5; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C577276:NEAT1 long non-coding RNA, human; D009363:Neoplasm Proteins; C568985:OCLN protein, human; D062793:Occludin; D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; C490301:SOX5 protein, human; D055755:SOXD Transcription Factors; C569042:TJP1 protein, human; D062725:Tight Junction Proteins; D062826:Zonula Occludens-1 Protein
keywords: Blood tumor-barrier; MiR-181d-5p; NEAT1; SOX5; Tight junction