title: Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140.
abstract: The blood-tumor barrier (BTB) forms a major obstacle in brain tumor therapy by preventing the delivery of sufficient quantities of therapeutic drugs. Long non-coding RNAs (lncRNAs) play important roles in both normal development and diseases including cancer. Here, we elucidated the expression of lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) and defined its functional role in the regulation of BTB function as well as its possible molecular mechanisms. Our results proved that MALAT1 expression was up-regulated in brain microvessels of human glioma and glioma endothelial cells (GECs) which were obtained by co-culturing endothelial cells with glioma cells. Functionally, knockdown of MALAT1 resulted in an impairment and increased the permeability of BTB as well as decreased the expression of ZO-1, occludin and claudin-5 in GECs. Further, there was reciprocal repression between MALAT1 and miR-140, and miR-140 mediated the effects that MALAT1 knockdown exerted. Mechanistic investigations defined that nuclear factor YA (NFYA), a CCAAT box-binding transcription factor, was a direct and functional downstream target of miR-140, which was involved in the MALAT1 knockdown induced regulation of BTB function. Furthermore, NFYA could up-regulate the promoter activities and bind to the promoters of ZO-1, occludin and claudin-5 in GECs. Taken together, we have demonstrated the fact that knockdown of MALAT1 resulted in the increased permeability of BTB, which might contribute to establishing potential therapeutic strategies for human gliomas.
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110122, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110122, 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 110004, People's Republic of China.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Xiaobai
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110122, People's Republic of China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110122, People's Republic of China.
authors.forename: Xihe
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Xi
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Teng
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, People's Republic of China; Institute of Pathology and Pathophysiology, 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: D001812:Blood-Brain Barrier / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability / Q000235:genetics; D045744:Cell Line, Tumor; D062507:Claudin-5 / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D062793:Occludin / Q000235:genetics; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics*; D062826:Zonula Occludens-1 Protein / Q000235:genetics
chemical_list: D023081:CCAAT-Binding Factor; D062507:Claudin-5; C557041:MALAT1 long non-coding RNA, human; D035683:MicroRNAs; C544302:Mirn140 microRNA, human; C492061:NFYA protein, human; D062793:Occludin; D062085:RNA, Long Noncoding; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein
keywords: Blood–tumor barrier; MALAT1; MiR-140; NFYA; Tight junction related proteins