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Inhibition of Nodal suppresses angiogenesis and growth of human gliomas

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
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Abstract

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.

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Acknowledgments

Shi-Yuan Cheng and Jia-Jean Yiin (University of Pittsburgh, Cancer Institute and Department of Pathology) provided us with invaluable suggestions in editing this manuscript. This study was supported by grants TSGH-C99-072, TSGH-C99-073, TSGH-C99-074, and TSGH-C99-149 (Dueng-Yuan Hueng) from the Tri-Service General Hospital; the grant B971113 from the Teh-Tzer Study Group for Human Medical Research Foundation, and in part by the Foundation for Advancement of Education, Sciences and Medicine, and grants DOH99-TD-B-111-003 and DOH99-TD-C-111-008 from Taiwan Department of Health for Taipei Medical University-the Center of Excellence for Clinical Trial and Research in Neuroscience, and the Center of Excellence for Cancer Research. We thank the technical support from the Functional and Micro-Magnetic Resonance Imaging Center supported by the National Research Program for Genomic Medicine, National Science Council, NSC95-3112-B-001-009.

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Authors and Affiliations

  1. 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 Hueng, Da-Tong Ju & Hsin-I Ma

  2. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC

    Dueng-Yuan Hueng, Huey-Kang Sytwu & Hsin-I Ma

  3. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC

    Gu-Jiun Lin & Huey-Kang Sytwu

  4. Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan, ROC

    Gu-Jiun Lin

  5. Department of General Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC

    Shing-Hwa Huang

  6. Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC

    Yuan-Wu Chen

  7. Institute of Biomedical Science, Academia Sinica, Nankang, Taipei, Taiwan, ROC

    Chen Chang

  8. Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC

    Shih-Ming Huang

  9. Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Center of Excellence for Cancer Research, Taipei, Taiwan, ROC

    Yi-Shian Yeh

  10. Department of Medical Laboratory Sciences and Biotechnology, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC

    Li-Wen Liu & Horng-Mo Lee

  11. Institute of Pharmaceutical Science and Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan, ROC

    Horng-Mo Lee

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  1. Dueng-Yuan Hueng
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Correspondence to Hsin-I Ma.

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Hueng, DY., Lin, GJ., Huang, SH. et al. Inhibition of Nodal suppresses angiogenesis and growth of human gliomas. J Neurooncol 104, 21–31 (2011). https://doi.org/10.1007/s11060-010-0467-3

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  • DOI: https://doi.org/10.1007/s11060-010-0467-3

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