miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways
Hui Wang, … , Huibo Wang, Xiao-Fan Wang
Hui Wang, … , Huibo Wang, Xiao-Fan Wang
Published September 9, 2014
Citation Information: J Clin Invest. 2014;124(10):4489-4502. https://doi.org/10.1172/JCI75284.
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Research Article Oncology

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

Hui Wang, Tao Sun, Jing Hu, Rui Zhang, Yanhua Rao, Shuai Wang, Rui Chen, Roger E. McLendon, Allan H. Friedman, Stephen T. Keir, Darell D. Bigner, Qi-Jing Li, Huibo Wang, Xiao-Fan Wang

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Figure 1

Identification of miR-33a as a top candidate among those differentially expressed miRNAs between GICs and non-GICs isolated from fresh GBM patient specimens and xenografts.

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Identification of miR-33a as a top candidate among those differentially ...
(A) A scatter dot plot shows the expression pattern of miR-33a in GICs enriched by defined medium compared with their non-GIC counterparts in 16 clinical GBM specimens, as detected by qRT-PCR. RNU6 was used as an internal control. (B) Relative expression levels of miR-33a in GICs enriched by CD133+selection from 3 xenograft tumor lines compared with their CD133– counterparts, as detected by qRT-PCR. RNU6 was used as an internal control. (C) Expression levels of miR-33a were examined by qRT-PCR in the SSEA-1–positive versus SSEA-1–negative cells isolated from D456MG through flow cytometry. (D) The ISH analysis of miR-33a was performed on 107 human GBM tumor tissues, and correlation between miR-33a levels and overall patient survival was shown by the Kaplan-Meier curve, with high (n = 70) or low (n = 37) miR-33a expression. *P < 0.05; **P < 0.01.