title: Tumorigenic potential of miR-18A* in glioma initiating cells requires NOTCH-1 signaling.
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.
authors.affiliation: Université de Nice-Sophia, Nice, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Turchi
authors.forename: David N
authors.initials: DN
authors.lastname: Debruyne
authors.forename: Fabien
authors.initials: F
authors.lastname: Almairac
authors.forename: Virginie
authors.initials: V
authors.lastname: Virolle
authors.forename: Mohamed
authors.initials: M
authors.lastname: Fareh
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Neirijnck
authors.forename: Fanny
authors.initials: F
authors.lastname: Burel-Vandenbos
authors.forename: Philippe
authors.initials: P
authors.lastname: Paquis
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Obberghen-Schilling
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.forename: Thierry
authors.initials: T
authors.lastname: Virolle
mesh_terms: D000368:Aged; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D015536:Down-Regulation; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C496666:DLL3 protein, human; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; C522576:MIRN18A microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C509239:SHH protein, human
keywords: Delta like 3 protein; Extracellular signal-regulated kinase; Glioblastoma; NOTCH; Sonic hedgehog; miR-18a*