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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / therapy
  • Cell Proliferation / drug effects
  • Gene Expression Regulation, Neoplastic
  • Genome, Human
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Humans
  • Mice
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / biosynthesis*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Oligonucleotides / administration & dosage*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • MIRN148 microRNA, human
  • MIRN31 microRNA, human
  • MicroRNAs
  • Oligonucleotides