期刊
GENES & DEVELOPMENT
卷 29, 期 7, 页码 732-745出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.257394.114
关键词
miR-182; Bcl2L12; c-Met; HIF2A; glioblastoma; nanotechnology; spherical nucleic acids
资金
- Center for Cancer Nanotechnology Excellence (CCNE) initiative of the National Institutes of Health (NIH) [U54 CA151880]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/NIH [R01AR060810, R21AR062898]
- Dixon Translational Research Grants Initiative of the Northwestern Memorial Foundation
- American Cancer Society
- James S. MacDonnell 21st Century Initiative
- Coffman Charitable Trust
- NIH [P01 CA095616, U01 CA141508, U24 CA143845]
- Ben and Catherine Ivy Foundation
- NIH National Cancer Institute (NCI) [F32CA171949]
- Northwestern University International Institute of Nanotechnology
- NCI Cancer Center [P30 CA060553]
- Quantitative Bioelemental Imaging Center by NASA Ames Research Center [NNA06CB93G]
- Defense Advanced Projects Agency (DARPA) [HR0011-13-2-0018]
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 2a (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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