Roundabout4 Suppresses Glioma-Induced Endothelial Cell Proliferation, Migration and Tube Formation in Vitro by Inhibiting VEGR2-Mediated PI3K/AKT and FAK Signaling Pathways

被引：45
作者：
Cai, Heng [1 ]
Xue, Yixue [2 ,3 ]
Li, Zhen [1 ]
Hu, Yi [1 ]
Wang, Zhenhua [4 ]
Liu, Wenjing [5 ]
Li, Zhiqing [2 ,3 ]
Liu, Yunhui [1 ]
机构：
[1] China Med Univ, Shengjing Hosp, Dept Neurosurg, Shenyang 110004, Peoples R China
[2] China Med Univ, Affiliated Hosp 1, Coll Basic Med, Dept Neurobiol, Shenyang 110004, Peoples R China
[3] China Med Univ, Affiliated Hosp 1, Inst Pathol & Pathophysiol, Shenyang 110004, Peoples R China
[4] China Med Univ, Affiliated Hosp 1, Dept Physiol, Shenyang 110004, Peoples R China
[5] China Med Univ, Affiliated Hosp 1, Dept Geriatr, Shenyang 110004, Peoples R China
来源：
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY | 2015年 / 35卷 / 05期
关键词：
Roundabout4; Angiogenesis; Endothelial cell; Glioma; Vascular endothelial growth factor; GROWTH-FACTOR; PATHOLOGICAL ANGIOGENESIS; VESSEL INTEGRITY; TUMOR; RECEPTOR; BRAIN; ACTIVATION; EXPRESSION; INVASION; MIDLINE;
D O I：
10.1159/000373982
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Background and Aims: Endothelial cell (EC) proliferation, migration, and tube formation are the critical steps for tumor angiogenesis, which is involved in the formation of new tumor blood vessels. Roundabout4 (Robo4), a new member of Robo proteins family, is specifically expressed in endothelial cells. This study aimed to investigate the effects of Robo4 on glioma-induced endothelial cell proliferation, migration and tube formation in vitro. Methods and Results: We found that Robo4 was endogenously expressed in Human Brain Microvascular Endothelial Cells (HBMECs), while Robo4 was significantly down-regulated in endothelial cells cultured in glioma conditioned medium. Robo4 over-expression remarkably suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro. In addition, Robo4 influenced the glioma-induced angiogenesis via binding to its ligand Slit2. Further studies demonstrated that the knockdown of Robo4 up-regulated the phosphorylation of VEGFR2, PI3K, AKT and FAK in EC cultured in glioma conditioned medium. VEGFR2 inhibitor SU-1498, AKT inhibitor LY294002 and FAK inhibitor 14 (FAK inhibitor) blocked the Robo4 knockdown-mediated alteration in glioma angiogenesis in vitro. Conclusion: Our results proved that Robo4 suppressed glioma-induced endothelial cell proliferation, migration and tube formation in vitro by inhibiting VEGR2-mediated activation of PI3K/AKT and FAK signaling pathways. Copyright (C) 2015 S. Karger AG, Basel
引用
收藏
页码：1689 / 1705
页数：17
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[1]   Akt1/protein kinase Bα is critical for ischemic and VEGF-mediated angiogenesis [J].
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Yu, J ;
Zoellner, S ;
Iwakiri, Y ;
Skurk, C ;
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Ouchi, N ;
Easton, RM ;
Galasso, G ;
Birnbaum, MJ ;
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Sessa, WC .
JOURNAL OF CLINICAL INVESTIGATION, 2005, 115 (08) :2119-2127
[2]   The role of Slit-Robo signaling in the generation, migration and morphological differentiation of cortical interneurons [J].
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Hernadez-Miranda, Luis R. ;
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Sundaresan, Vasi ;
Rabbitts, Terence H. ;
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Parnavelas, John G. .
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[3]   Angiogenesis and Anti-Angiogenic Molecularly Targeted Therapies in Malignant Gliomas [J].
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[4]   Quantification of SLIT-ROBO transcripts in hepatocellular carcinoma reveals two groups of genes with coordinate expression [J].
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Yagci, Tamer .
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[5]   Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor [J].
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Hao, Yueling ;
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Hjelmeland, Anita B. ;
Shi, Oing ;
McLendon, Roger E. ;
Bigner, Darell D. ;
Rich, Jeremy N. .
CANCER RESEARCH, 2006, 66 (16) :7843-7848
[6]   roundabout4 is essential for angiogenesis in vivo [J].
Bedell, VM ;
Yeo, SY ;
Park, KW ;
Chung, J ;
Seth, P ;
Shivalingappa, V ;
Zhao, JH ;
Obara, T ;
Sukhatme, VP ;
Drummond, IA ;
Li, DY ;
Ramchandran, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (18) :6373-6378
[7]   The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis [J].
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Bellail, AC ;
Van Meir, EG .
NEURO-ONCOLOGY, 2005, 7 (02) :122-133
[8]   Slit proteins bind robe receptors and have an evolutionarily conserved role in repulsive axon guidance [J].
Brose, K ;
Bland, KS ;
Wang, KH ;
Arnott, D ;
Henzel, W ;
Goodman, CS ;
Tessier-Lavigne, M ;
Kidd, T .
CELL, 1999, 96 (06) :795-806
[9]   Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo [J].
Chen, JH ;
Somanath, PR ;
Razorenova, O ;
Chen, WS ;
Hay, N ;
Bornstein, P ;
Byzova, TV .
NATURE MEDICINE, 2005, 11 (11) :1188-1196
[10]   Angiogenesis as a Therapeutic Target in Malignant Gliomas [J].
Chi, Andrew S. ;
Sorensen, A. Gregory ;
Jain, Rakesh K. ;
Batchelor, Tracy T. .
ONCOLOGIST, 2009, 14 (06) :621-636
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