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Mol Ther. 2015 Jul;23(7):1234-1247. doi: 10.1038/mt.2015.72. Epub 2015 Apr 23.

The Cancer Genome Atlas Analysis Predicts MicroRNA for Targeting Cancer Growth and Vascularization in Glioblastoma.

Author information

1
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA.
3
Cancer Research and Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
4
Regulus Therapeutics, Inc., San Diego, California, USA.
5
Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
6
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA; Current Address: Department of Bioengineering, University of Illinois, Urbana-Champaign, Illinois, USA; Current Address: Department of Physics, University of Illinois, Urbana-Champaign, Illinois, USA.
7
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
8
Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Electronic address: akrichevsky@rics.bwh.harvard.edu.

Abstract

Using in silico analysis of The Cancer Genome Atlas (TCGA), we identified microRNAs associated with glioblastoma (GBM) survival, and predicted their functions in glioma growth and progression. Inhibition of two "risky" miRNAs, miR-148a and miR-31, in orthotopic xenograft GBM mouse models suppressed tumor growth and thereby prolonged animal survival. Intracranial tumors treated with uncomplexed miR-148a and miR-31 antagomirs exhibited reduced proliferation, stem cell depletion, and normalized tumor vasculature. Growth-promoting functions of these two miRNAs were, in part, mediated by the common target, the factor inhibiting hypoxia-inducible factor 1 (FIH1), and the downstream pathways involving hypoxia-inducible factor HIF1α and Notch signaling. Therefore, miR-31 and miR-148a regulate glioma growth by maintaining tumor stem cells and their niche, and providing the tumor a way to activate angiogenesis even in a normoxic environment. This is the first study that demonstrates intratumoral uptake and growth-inhibiting effects of uncomplexed antagomirs in orthotopic glioma.

PMID:
25903473
PMCID:
PMC4817797
DOI:
10.1038/mt.2015.72
[Indexed for MEDLINE]
Free PMC Article

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