Inhibition of Nodal suppresses angiogenesis and growth of human gliomas.
Angiogenesis is the hallmark of malignant gliomas positively correlated with the vascular endothelial growth factor (VEGF) expression. We previously reported that expression levels of Nodal, a member of transforming growth factor-β super family, correlate with the malignant invasive behavior of human glioma cells. In this study, we show that knockdown of Nodal suppresses glioma angiogenesis by inhibition of VEGF. In human primary glioma specimens, expression of Nodal positively correlates with WHO glioma tumor grades and expression of VEGF in the corresponding glioma specimens. In human U87MG glioma cells, knockdown of endogenous Nodal by RNA interference (RNAi) significantly decreases colony formation and secretion of VEGF. In vivo, cellular depletion of Nodal in U87MG inhibited brain glioma growth and prolonged the survival of mice with U87MG/shNodal glioma compared with controls. Inhibition of Nodal suppressed tumor vessel growth in U87MG gliomas. Using Nodal inhibitor (SB431542), silencing Nodal, or overexpressing Nodal in the U87MG, GBM8401, and GBM glioma cells, our further experiments revealed that Nodal-induced VEGF expression might, at least in part, mediate through the ERK1/2-HIF-1α-mediated signaling pathway. Taken together, our data revealed that alteration of Nodal expression in glioma cells resulted in changes to VEGF secretion, and subsequent colony formation, in vivo tumor growth, and angiogenesis, all of which are consistent with the regulation of VEGF through the ERK1/2-HIF-1α-mediated signaling, suggesting that Nodal may serve as a potential therapeutic target for the treatment of human gliomas.
Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, 325, Sec. 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan, ROC.
Dueng-Yuan
DY
Hueng
Gu-Jiun
GJ
Lin
Shing-Hwa
SH
Huang
Li-Wen
LW
Liu
Da-Tong
DT
Ju
Yuan-Wu
YW
Chen
Huey-Kang
HK
Sytwu
Chen
C
Chang
Shih-Ming
SM
Huang
Yi-Shian
YS
Yeh
Horng-Mo
HM
Lee
Hsin-I
HI
Ma
D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D004149:Dioxoles / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C526007:NODAL protein, human; D055457:Nodal Protein; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one