Tumorigenic Potential of miR-18A* in Glioma Initiating Cells Requires NOTCH-1 Signaling§

Authors

  • Laurent Turchi,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    Search for more papers by this author
  • David N. Debruyne,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    Search for more papers by this author
  • Fabien Almairac,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    3. Service de NeurochirurgieHôpital Pasteur, CHU de Nice, Nice, France
    Search for more papers by this author
  • Virginie Virolle,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    Search for more papers by this author
  • Mohamed Fareh,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    Search for more papers by this author
  • Yasmine Neirijnck,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    Search for more papers by this author
  • Fanny Burel-Vandenbos,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    3. Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice, France
    Search for more papers by this author
  • Philippe Paquis,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    3. Service de NeurochirurgieHôpital Pasteur, CHU de Nice, Nice, France
    Search for more papers by this author
  • Marie-Pierre Junier,

    1. Plasticité Gliale, Centre de Psychiatrie et Neurosciences, UMR 894 INSERM/Faculté de Médecine, Université Paris Descartes, Paris, France
    Search for more papers by this author
  • Ellen Van Obberghen-Schilling,

    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    Search for more papers by this author
  • Hervé Chneiweiss,

    1. Plasticité Gliale, Centre de Psychiatrie et Neurosciences, UMR 894 INSERM/Faculté de Médecine, Université Paris Descartes, Paris, France
    Search for more papers by this author
  • Thierry Virolle

    Corresponding author
    1. Université de Nice-Sophia AntipolisCNRS UMR7277, INSERM UMR1091, Nice, France
    2. Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, Nice, France
    • Institut de Biologie Valrose, CNRS UMR7277, INSERM UMR1091, UNS, Parc Valrose, 06108 Nice, France
    Search for more papers by this author
    • Telephone: 04 93 37 76 20


  • Author contributions: L.T. : conception and design, manuscript writing, data analysis and interpretation, and collection and or assembly of data; D.N.D.: conception and design, data analysis and interpretation, and collection and or assembly of data; F.A., V.V., M. F., and Y.N.: conception and design and data analysis and interpretation; F.B. and M.J.: provision of study material of patients and data analysis and interpretation; P.P.: provision of study material of patients; E.V.O.: manuscript writing; H.C.: provision of study material of patients and manuscript writing; T. V.: conception and design, manuscript writing, data analysis and interpretation, collection and or assembly of data, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS March 26, 2013.

Abstract

Stem cell-like properties of glioma initiating cells (GiCs) fuel glioblastoma (GBM) development by providing the different cell types that comprise the tumor. It is therefore likely that the molecular circuitries that regulate their decision to self-renew or commit to a more differentiated state may offer targets for future innovative therapies. In previous micro-RNA profiling studies to search for regulators of stem cell plasticity, we identified miR-18a* as a potential candidate and its expression correlated with the stemness state. Here, using human GiCs we found that miR-18a* expression promotes clonal proliferation in vitro and tumorigenicity in vivo. Mechanistically, ERK-dependent induction of miR-18a* directly represses expression of DLL3, an autocrine inhibitor of NOTCH, thus enhancing the level of activated NOTCH-1. Activated NOTCH-1 in turn is required for sustained ERK activation. This feed-forward loop, driven by miR-18a*, is required to turn on the SHH-GLI-NANOG network, essential for GiC self-renewal. Hence, by tightly regulating expression of DLL3, miR-18a* constitutes an important signaling mediator for fine tuning the level of GiC self-renewal. STEM Cells2013;31:1252–1265

Ancillary