title: miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways.
abstract: Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Rao
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D012008:Recurrence; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014466:Ultraviolet Rays
chemical_list: C550416:MIRN33a microRNA, human; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D012333:RNA, Messenger; D051880:Receptors, Notch; D017868:Cyclic AMP-Dependent Protein Kinases