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Biochim Biophys Acta. 2016 Feb;1859(2):324-38. doi: 10.1016/j.bbagrm.2015.11.008. Epub 2015 Nov 24.

Knockdown of long non-coding RNA MALAT1 increases the blood-tumor barrier permeability by up-regulating miR-140.

Author information

1
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.
2
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
3
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.

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.

KEYWORDS:

Blood–tumor barrier; MALAT1; MiR-140; NFYA; Tight junction related proteins

PMID:
26619802
DOI:
10.1016/j.bbagrm.2015.11.008
[Indexed for MEDLINE]

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