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Targeting Netrin-1 in glioblastoma stem-like cells inhibits growth, invasion, and angiogenesis

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Tumor Biology

Abstract

Glioblastoma (GBM) is an aggressive malignant brain tumor that still lacks effective therapy. Glioblastoma stem cells (GBM-SCs) were identified to contribute to aggressive phenotypes and poor clinical outcomes for GBM. Netrin-1, an axon guidance molecule, has been found in several tumors in adults. However, the role of Netrin-1 in GBM-SCs remains largely unknown. In this study, CD133-positive U251 GBM cells were used as a putative GBM-SC population to identify the functions of Netrin-1. Using lentiviral transduction, Netrin-1 miR RNAi vectors were transduced into CD133-positive U251 cells. We demonstrated that cell proliferation and survival were decreased following targeted deletion of Netrin-1. Cell invasion was dramatically diminished in Netrin-1 knockdown GBM-SCs. Moreover, Netrin-1 knockdown GBM-SCs exhibited less proangiogenic activity. In conclusion, Netrin-1 may represent a therapeutic target in glioblastoma.

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Acknowledgments

The authors thank to the Faculty of Medical Technology, Mahidol University for facility support, Siriraj Core Research Facility (SiCRF) for assistance with flow cytometry and members of Siriraj Center of Excellence for Stem Cell Research (SiSCR) for their supports and helpful discussions.

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Authors and Affiliations

  1. Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, Thailand

    Tanwarat Sanvoranart & Aungkura Supokawej

  2. Division of Cell Biology, Department of Pre-clinical Sciences, Faculty of Medicine, Thammasat University, Pathumthani, Thailand

    Pakpoom Kheolamai

  3. Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkoknoi, Bangkok, 10700, Thailand

    Yaowalak U-pratya & Surapol Issaragrisil

  4. Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkoknoi, Bangkok, 10700, Thailand

    Yaowalak U-pratya & Surapol Issaragrisil

  5. Division of Neurology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkoknoi, Bangkok, 10700, Thailand

    Niphon Poungvarin & Sith Sathornsumetee

  6. NANOTEC-Mahidol University Center of Excellence in Nanotechnology for Cancer Diagnosis and Treatment, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wang Lang Road, Bangkoknoi, Bangkok, 10700, Thailand

    Sith Sathornsumetee

Authors
  1. Tanwarat Sanvoranart
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  2. Aungkura Supokawej
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  6. Sith Sathornsumetee
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Correspondence to Sith Sathornsumetee or Surapol Issaragrisil.

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Funding

This research project was funded by grants from Mahidol University, Thailand Research Fund (Grant no. RTA 488-0007), the Commission on Higher Education (Grant no. CHE-RES-RG-49). S.I. is a Senior Research Scholar of Thailand Research Fund. T.S. was supported by the Thailand Research Funds through the Royal Golden Jubilee PhD Program (PhD/0199/2550). S.S. is partially supported by grants from the National Nanotechnology Center (NANOTEC), NSTDA, Ministry of Science and Technology through its program of Center of Excellence Network and Faculty of Medicine Siriraj Hospital, Mahidol University.

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Sanvoranart, T., Supokawej, A., Kheolamai, P. et al. Targeting Netrin-1 in glioblastoma stem-like cells inhibits growth, invasion, and angiogenesis. Tumor Biol. 37, 14949–14960 (2016). https://doi.org/10.1007/s13277-016-5314-5

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  • DOI: https://doi.org/10.1007/s13277-016-5314-5

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