[HTML][HTML] miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways

H Wang, T Sun, J Hu, R Zhang, Y Rao… - The Journal of …, 2014 - Am Soc Clin Investig
H Wang, T Sun, J Hu, R Zhang, Y Rao, S Wang, R Chen, RE McLendon, AH Friedman…
The Journal of clinical investigation, 2014Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation