MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma

Fotini M. Kouri, Lisa A. Hurley, Weston L. Daniel, Emily S. Day, Youjia Hua, Liangliang Hao, Chian Yu Peng, Timothy J. Merkel, Markus A. Queisser, Carissa Ritner, Hailei Zhang, C. David James, Jacob I. Sznajder, Lynda Chin, David A. Giljohann, John A. Kessler, Marcus E. Peter, Chad A. Mirkin, Alexander H. Stegh*

*Corresponding author for this work

Research output: Contribution to journalArticle

117 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)732-745
Number of pages14
JournalGenes and Development
Volume29
Issue number7
DOIs
StatePublished - Jan 1 2015

Keywords

  • Bcl2L12
  • Glioblastoma
  • HIF2A
  • Nanotechnology
  • Spherical nucleic acids
  • c-Met
  • miR-182

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Kouri, F. M., Hurley, L. A., Daniel, W. L., Day, E. S., Hua, Y., Hao, L., Peng, C. Y., Merkel, T. J., Queisser, M. A., Ritner, C., Zhang, H., David James, C., Sznajder, J. I., Chin, L., Giljohann, D. A., Kessler, J. A., Peter, M. E., Mirkin, C. A., & Stegh, A. H. (2015). MiR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes and Development, 29(7), 732-745. https://doi.org/10.1101/gad.257394.114