MiR-181a Regulates Blood-Tumor Barrier Permeability by Targeting Krüppel-Like Factor 6

Ma, Jun; Yao, Yilong; Wang, Ping; Liu, Yunhui; Zhao, Liye; Li, Zhen; Li, Zhiqing; Xue, Yixue

doi:10.1038/jcbfm.2014.152

Cited by 60 publications

(42 citation statements)

References 37 publications

(40 reference statements)

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“…Several studies of micro-RNAs and other drugs on the permeability of the BTB showed similar results. For example, overexpression of miR-34c, miR-181a, and EMAPII increased the permeability of the BTB by changing the expressions and distributions of tight junctionrelated proteins ZO-1, claudin-5, and occludin (Ma et al, 2014b;Li et al, 2015;Zhao et al, 2015), and the common feature is that they increased the permeability of the BTB through paracellular pathways.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of miR‐18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood–tumor barrier via Krüppel‐like factor 4‐mediated downregulation of zonula occluden‐1, claudin‐5, and occludin

Zhao

Wang

et al. 2015

J of Neuroscience Research

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miR-18a represses angiogenesis and tumor evasion by weakening vascular endothelial growth factor and transforming growth factor-β signaling to prolong the survival of glioma patients, although it is thought to be an oncogene. This study investigates the potential effects of miR-18a on the permeability of the blood-tumor barrier (BTB) and its possible molecular mechanisms. An in vitro BTB model was successfully established. The endogenous expression of miR-18a in glioma vascular endothelial cells (GECs) was significantly lower than that in normal vascular ECs, and the overexpression of miR-18a significantly increased the permeability of the BTB as well as downregulating the mRNA and protein expressions of tight junction-related proteins zonula occluden-1 (ZO-1), claudin-5, and occludin in GECs. Dual luciferase reporter assays revealed that miR-18a bound to the 3'-untranslated region (3'UTR) of myocyte enhancer factor 2D (MEF2D). The overexpression of both miR-18a and MEF2D with the 3'UTR significantly weakened the effect caused by miR-18a of decreasing the mRNA and protein expressions of ZO-1, claudin-5 and occludin and of increasing the permeability of the BTB. Chromatin immunoprecipitation showed that MEF2D could directly bind to KLF4 promoter. This study shows that miR-18a targets and negatively regulates MEF2D, which further regulates tight junction-related proteins ZO-1, claudin-5, and occludin through transactivation of KLF4 and, finally, changes the permeability of the BTB. MiR-18a should garner growing attention because it might serve as a potential target in opening the BTB and providing a new strategy for the treatment of gliomas.

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Section: Discussionmentioning

confidence: 99%

Overexpression of miR‐18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood–tumor barrier via Krüppel‐like factor 4‐mediated downregulation of zonula occluden‐1, claudin‐5, and occludin

Zhao

Wang

et al. 2015

J of Neuroscience Research

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“…The in vitro BTB model was established by coculturing hCMEC/D3 with U87-MG in a Transwell permeable support system (0.4 mm pore size; Corning, Corning, NY, USA) as previously described (25). Briefly, hCMEC/D3s cells were seeded at 2 3 10 5 per well in 6-well plates on the upper side of the inserts with EBM-2.…”

Section: Establishment Of Btb Model In Vitromentioning

confidence: 99%

miR‐132‐3p boosts caveolae‐mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav‐1 signaling pathway

Cai

Zhang

et al. 2018

The FASEB Journal

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Blood-brain tumor barrier (BTB) impedes the transportation of antitumor therapeutic drugs into brain tumors. Its mechanism is still unknown, but learning how to improve the BTB permeability is critical for drug intervention. Recently, microRNAs (miRNAs) have appeared as regulation factors of numerous biologic processes and therapeutic targets of diverse diseases. In this study, we have identified that miR-132-3p is an essential miRNA by increasing the transcellular transport through the BTB. We found that miR-132-3p expression was significantly up-regulated in glioma endothelial cells (GECs). Furthermore we showed that miR132-3p greatly induced the endocytosis of cholera toxin subunit B and FITC-bovine serum albumin and up-regulated the expression of p-PKB, p-Src and Tyr14 phosphorylation of caveolin-1 (p-Cav-1), while phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression was markedly down-regulated in GECs. Our results identify PTEN as a direct and functional downstream target of miR-132-3p, which is involved in the regulation of p-PKB, p-Src, and p-Cav-1. The inhibitors for PI3K and Src significantly reversed the increase of p-Cav-1 induced by miR-132-3p. Moreover, overexpression of PTEN greatly reduced the endocytosis of cholera toxin subunit B and the up-regulation of p-Cav-1 induced by agomiR132-3p, suggesting that miR132-3p increases the endothelial permeability by inhibition of PTEN expression. In addition, miR132-3p significantly increased the delivery of doxorubicin across the BTB in vitro and contributed to the accumulation of doxorubicin within the brain tumor tissue. Our results show that miR-132-3p contributes to the increased permeability of BTB by targeting PTEN/PI3K/PKB/Src/Cav-1, thereby revealing a novel drug target for the treatment of brain gliomas.-Gu, Y., Cai, R., Zhang, C., Xue, Y., Pan, Y., Wang, J., Zhang, Z. miR-132-3p boosts caveolae-mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav-1 signaling pathway.

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“…While EC-EV released miRNA are understood to play a distinct role in endothelial function, how miRNAs derived from EC-EVs contribute to the characteristic loss of coordination leading to development of sepsis remains unclear (►Table 2). [75][76][77][78][103][104][105][106][107]…”

Section: Extrinsic Endothelial Mirna Dysregulation In Vascular Diseasementioning

confidence: 99%

The Evolving Role of MicroRNAs in Endothelial Cell Dysfunction in Response to Infection

Watkin

Fitzpatrick

Kerrigan

2018

Semin Thromb Hemost

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The microRNAs are short noncoding RNA molecules responsible for translational repression and silencing of target genes via binding to the mRNA. They are found in all eukaryotic cells and play a critical role in virtually all physiological processes, including within the cardiovascular system where they influence cellular development, differentiation, cardiovascular function, hemostasis, and programmed cell death. Dysregulated microRNA expression is associated with several conditions ranging from cancer and autoimmune disease to infection. Progressively, it has become increasingly clear that microRNAs are important components of the host response to microbes. The cardiovascular system, coupled with cells of the innate immune system, provide the initial interaction and first response to microbial infection, respectively. This review presents the current state of knowledge regarding the role of microRNAs with emphasis on their role in controlling endothelial cell function.

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MiR-181a Regulates Blood-Tumor Barrier Permeability by Targeting Krüppel-Like Factor 6

Cited by 60 publications

References 37 publications

Overexpression of miR‐18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood–tumor barrier via Krüppel‐like factor 4‐mediated downregulation of zonula occluden‐1, claudin‐5, and occludin

Overexpression of miR‐18a negatively regulates myocyte enhancer factor 2D to increase the permeability of the blood–tumor barrier via Krüppel‐like factor 4‐mediated downregulation of zonula occluden‐1, claudin‐5, and occludin

miR‐132‐3p boosts caveolae‐mediated transcellular transport in glioma endothelial cells by targeting PTEN/PI3K/PKB/Src/Cav‐1 signaling pathway

The Evolving Role of MicroRNAs in Endothelial Cell Dysfunction in Response to Infection

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