miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma
- Fotini M. Kouri1,2,
- Lisa A. Hurley1,2,
- Weston L. Daniel3,
- Emily S. Day4,5,
- Youjia Hua6,7,
- Liangliang Hao4,5,
- Chian-Yu Peng1,2,
- Timothy J. Merkel4,5,
- Markus A. Queisser8,
- Carissa Ritner1,2,
- Hailei Zhang9,10,11,12,13,
- C. David James14,
- Jacob I. Sznajder8,
- Lynda Chin9,10,11,12,13,
- David A. Giljohann3,
- John A. Kessler1,2,
- Marcus E. Peter6,7,
- Chad A. Mirkin4,5 and
- Alexander H. Stegh1,2,4,5
- 1Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 2The Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
- 3AuraSense Therapeutics, Skokie, Illinois 60077, USA;
- 4Department of Chemistry, Northwestern University, Evanston, Illinois 60208, USA;
- 5International Institute for Nanotechnology, Northwestern University, Evanston, Illinois 60208, USA;
- 6Division Hematology/Oncology, Feinberg School of Medicine, Chicago, Illinois 60611, USA;
- 7The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA;
- 8Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, USA;
- 9The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA;
- 10Harvard Medical School, Boston, Massachusetts 02115, USA;
- 11Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;
- 12Department of Genomic Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 13Institute for Applied Cancer Science, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 14Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, USA
- Corresponding author: a-stegh{at}northwestern.edu
Abstract
Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to tumor recurrence following initial response to therapy. Here, we identified miR-182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Repression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia-inducible factor 2α (HIF2A) is of central importance to miR-182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we synthesized miR-182-based spherical nucleic acids (182-SNAs); i.e., gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the blood–brain/blood–tumor barriers (BBB/BTB) in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.257394.114.
- Received February 25, 2014.
- Accepted February 26, 2015.
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