MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5
The blood-tumor barrier (BTB) hinders delivery of chemotherapeutic drugs to tumors in the brain; previous studies have shown that the BTB can be selectively opened by endothelial monocyte activating polypeptide-II (EMAP-II), but the specific mechanism involved remains elusive. In this study, we foun...
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Frontiers Media S.A.
2018-02-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00035/full |
| _version_ | 1811215786424926208 |
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| author | Liangyu Chen Liangyu Chen Liangyu Chen Yixue Xue Yixue Xue Yixue Xue Jian Zheng Jian Zheng Jian Zheng Xiaobai Liu Xiaobai Liu Xiaobai Liu Jing Liu Jing Liu Jing Liu Jiajia Chen Jiajia Chen Jiajia Chen Zhen Li Zhen Li Zhen Li Zhuo Xi Zhuo Xi Zhuo Xi Hao Teng Hao Teng Hao Teng Ping Wang Ping Wang Ping Wang Libo Liu Libo Liu Libo Liu Yunhui Liu Yunhui Liu Yunhui Liu |
| author_facet | Liangyu Chen Liangyu Chen Liangyu Chen Yixue Xue Yixue Xue Yixue Xue Jian Zheng Jian Zheng Jian Zheng Xiaobai Liu Xiaobai Liu Xiaobai Liu Jing Liu Jing Liu Jing Liu Jiajia Chen Jiajia Chen Jiajia Chen Zhen Li Zhen Li Zhen Li Zhuo Xi Zhuo Xi Zhuo Xi Hao Teng Hao Teng Hao Teng Ping Wang Ping Wang Ping Wang Libo Liu Libo Liu Libo Liu Yunhui Liu Yunhui Liu Yunhui Liu |
| author_sort | Liangyu Chen |
| collection | DOAJ |
| description | The blood-tumor barrier (BTB) hinders delivery of chemotherapeutic drugs to tumors in the brain; previous studies have shown that the BTB can be selectively opened by endothelial monocyte activating polypeptide-II (EMAP-II), but the specific mechanism involved remains elusive. In this study, we found that microRNA-429 (miR-429) expression in glioma vascular endothelial cells (GECs) was far lower than in human brain microvascular endothelial cells (ECs). miR-429 had lower expression in GECs and glioma tissues compared to ECs or normal tissues of the brain. Furthermore, miR-429 had lower expression in high grade glioma (HGG) than in low grade glioma (LGG). In in vitro BTB models, we also found that EMAP-II significantly increased BTB permeability, decreased expression of ZO-1, occludin and claudin-5 in GECs, in a time- and dose-dependent manner. EMAP-II greatly increased miR-429 expression in GECs of the BTB models in vitro. Overexpression of miR-429 in GECs significantly decreased the transepithelial electric resistance (TEER) values in BTB models, and led to enhanced horseradish peroxidase (HRP) flux. Overexpression of miR-429 in GECs significantly decreased the expression of tight junction (TJ)-associated proteins (ZO-1, occludin and claudin-5), and decreased the distribution continuity. Silencing of miR-429 in GECs increased the expression of TJ-associated proteins and the distribution continuity. The dual-luciferase reporter assay revealed that ZO-1 and occludin were target genes of miR-429, and we demonstrated that miR-429 overexpression markedly down-regulated protein expression of p70S6K, as well as its phosphorylation levels. The dual-luciferase reporter assay also showed that p70S6K was a target gene of miR-429; miR-429 overexpression down-regulated expression and phosphorylation levels of p70S6K, and also decreased phosphorylation levels of S6 and increased BTB permeability. Conversely, silencing of miR-429 increased the expression and phosphorylation levels of p70S6K, and increased phosphorylation levels of S6, while decreasing BTB permeability. In conclusion, the results indicated that EMAP-II caused an increase in miR-429 expression that directly targeted TJ-associated proteins, which were negatively regulated; on the other hand, miR-429 down-regulated the expression of TJ-associated proteins by targeting p70S6K, also negatively regulated. As a result, the BTB permeability increased. |
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| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-12T06:29:31Z |
| publishDate | 2018-02-01 |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-a377a20bbe044c509ae82c402faf76f92022-12-22T03:44:04ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-02-011110.3389/fnmol.2018.00035318303MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5Liangyu Chen0Liangyu Chen1Liangyu Chen2Yixue Xue3Yixue Xue4Yixue Xue5Jian Zheng6Jian Zheng7Jian Zheng8Xiaobai Liu9Xiaobai Liu10Xiaobai Liu11Jing Liu12Jing Liu13Jing Liu14Jiajia Chen15Jiajia Chen16Jiajia Chen17Zhen Li18Zhen Li19Zhen Li20Zhuo Xi21Zhuo Xi22Zhuo Xi23Hao Teng24Hao Teng25Hao Teng26Ping Wang27Ping Wang28Ping Wang29Libo Liu30Libo Liu31Libo Liu32Yunhui Liu33Yunhui Liu34Yunhui Liu35Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaDepartment of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, ChinaKey Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, ChinaKey Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, ChinaDepartment of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaDepartment of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaDepartment of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaDepartment of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, ChinaKey Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, ChinaKey Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, ChinaDepartment of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaDepartment of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaDepartment of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaDepartment of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, ChinaKey Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, ChinaKey Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, ChinaDepartment of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, ChinaKey Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, ChinaKey Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, ChinaDepartment of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, ChinaLiaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, ChinaKey Laboratory of Neuro-oncology in Liaoning Province, Shenyang, ChinaThe blood-tumor barrier (BTB) hinders delivery of chemotherapeutic drugs to tumors in the brain; previous studies have shown that the BTB can be selectively opened by endothelial monocyte activating polypeptide-II (EMAP-II), but the specific mechanism involved remains elusive. In this study, we found that microRNA-429 (miR-429) expression in glioma vascular endothelial cells (GECs) was far lower than in human brain microvascular endothelial cells (ECs). miR-429 had lower expression in GECs and glioma tissues compared to ECs or normal tissues of the brain. Furthermore, miR-429 had lower expression in high grade glioma (HGG) than in low grade glioma (LGG). In in vitro BTB models, we also found that EMAP-II significantly increased BTB permeability, decreased expression of ZO-1, occludin and claudin-5 in GECs, in a time- and dose-dependent manner. EMAP-II greatly increased miR-429 expression in GECs of the BTB models in vitro. Overexpression of miR-429 in GECs significantly decreased the transepithelial electric resistance (TEER) values in BTB models, and led to enhanced horseradish peroxidase (HRP) flux. Overexpression of miR-429 in GECs significantly decreased the expression of tight junction (TJ)-associated proteins (ZO-1, occludin and claudin-5), and decreased the distribution continuity. Silencing of miR-429 in GECs increased the expression of TJ-associated proteins and the distribution continuity. The dual-luciferase reporter assay revealed that ZO-1 and occludin were target genes of miR-429, and we demonstrated that miR-429 overexpression markedly down-regulated protein expression of p70S6K, as well as its phosphorylation levels. The dual-luciferase reporter assay also showed that p70S6K was a target gene of miR-429; miR-429 overexpression down-regulated expression and phosphorylation levels of p70S6K, and also decreased phosphorylation levels of S6 and increased BTB permeability. Conversely, silencing of miR-429 increased the expression and phosphorylation levels of p70S6K, and increased phosphorylation levels of S6, while decreasing BTB permeability. In conclusion, the results indicated that EMAP-II caused an increase in miR-429 expression that directly targeted TJ-associated proteins, which were negatively regulated; on the other hand, miR-429 down-regulated the expression of TJ-associated proteins by targeting p70S6K, also negatively regulated. As a result, the BTB permeability increased.http://journal.frontiersin.org/article/10.3389/fnmol.2018.00035/fullblood-tumor barrierEMAP-IImiR-429p70S6Ks6K |
| spellingShingle | Liangyu Chen Liangyu Chen Liangyu Chen Yixue Xue Yixue Xue Yixue Xue Jian Zheng Jian Zheng Jian Zheng Xiaobai Liu Xiaobai Liu Xiaobai Liu Jing Liu Jing Liu Jing Liu Jiajia Chen Jiajia Chen Jiajia Chen Zhen Li Zhen Li Zhen Li Zhuo Xi Zhuo Xi Zhuo Xi Hao Teng Hao Teng Hao Teng Ping Wang Ping Wang Ping Wang Libo Liu Libo Liu Libo Liu Yunhui Liu Yunhui Liu Yunhui Liu MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5 Frontiers in Molecular Neuroscience blood-tumor barrier EMAP-II miR-429 p70S6K s6K |
| title | MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5 |
| title_full | MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5 |
| title_fullStr | MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5 |
| title_full_unstemmed | MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5 |
| title_short | MiR-429 Regulated by Endothelial Monocyte Activating Polypeptide-II (EMAP-II) Influences Blood-Tumor Barrier Permeability by Inhibiting the Expressions of ZO-1, Occludin and Claudin-5 |
| title_sort | mir 429 regulated by endothelial monocyte activating polypeptide ii emap ii influences blood tumor barrier permeability by inhibiting the expressions of zo 1 occludin and claudin 5 |
| topic | blood-tumor barrier EMAP-II miR-429 p70S6K s6K |
| url | http://journal.frontiersin.org/article/10.3389/fnmol.2018.00035/full |
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