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Knocking down nucleolin expression in gliomas inhibits tumor growth and induces cell cycle arrest

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Abstract

Nucleolin is a multifunctional protein whose expression often correlates with increased cellular proliferation. While the expression of nucleolin is often elevated in numerous cancers, its expression in normal human brain and in astrocytomas has not been previously reported. Using paraffin-embedded sections from normal adult autopsy specimens and glioma resection specimens, we demonstrate that nucleolin expression is limited in the normal human brain specifically to mature neurons, ependymal cells, and granular cells of the dentate gyrus. While astrocytes in the normal human brain do not express nucleolin at significant levels, glioblastoma cell lines and primary human astrocytoma cells exhibit considerable nucleolin expression. Reduction of nucleolin expression through siRNA-mediated knockdown in the U87MG glioblastoma cell line caused a dramatic decrease in cell proliferation and induced cell cycle arrest in vitro. Moreover, conditional siRNA knockdown of nucleolin expression in U87MG intracranial xenografts in nude mice caused dramatic reduction in tumor size. Taken together, these results implicate nucleolin in the regulation of human astrocytoma proliferation in vitro and tumorigenicity in vivo and suggest that nucleolin may represent a potential novel therapeutic target for astrocytomas.

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Acknowledgments

This research was supported in part by the Children’s Discovery Institute (MC-LI-2009-03R, JRL) and by P50 CA94056 (DPW).

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None.

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Authors and Affiliations

  1. Department of Neurological Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8057, St. Louis, MO, 63110, USA

    Zhiqiang Xu, Neel Joshi, Patrice Bittner, Sara Taylor & Jeffrey R. Leonard

  2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA

    Ashima Agarwal & Sonika Dahiya

  3. BRIGHT Institute, Washington University School of Medicine, St. Louis, MO, USA

    Erin Smith, David Piwnica-Worms & Jason Weber

  4. Departments of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA

    David Piwnica-Worms

  5. Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

    Jason Weber

  6. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA

    David Piwnica-Worms

  7. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

    Jeffrey R. Leonard

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  1. Zhiqiang Xu
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Correspondence to Jeffrey R. Leonard.

Additional information

Precis: This work shows the importance of nucleolin in regulating glioma growth and suggests regulation of nucleolin may serve as a valuable therapeutic target in treatment of gliomas.

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Xu, Z., Joshi, N., Agarwal, A. et al. Knocking down nucleolin expression in gliomas inhibits tumor growth and induces cell cycle arrest. J Neurooncol 108, 59–67 (2012). https://doi.org/10.1007/s11060-012-0827-2

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  • DOI: https://doi.org/10.1007/s11060-012-0827-2

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