The miR-223/nuclear factor I-A axis regulates glial precursor proliferation and tumorigenesis in the CNS

J Neurosci. 2013 Aug 14;33(33):13560-8. doi: 10.1523/JNEUROSCI.0321-13.2013.

Abstract

Contemporary views of tumorigenesis regard its inception as a convergence of genetic mutation and developmental context. Glioma is the most common and deadly malignancy in the CNS; therefore, understanding how regulators of glial development contribute to its formation remains a key question. Previously we identified nuclear factor I-A (NFIA) as a key regulator of developmental gliogenesis, while miR-223 has been shown to repress NFIA expression in other systems. Using this relationship as a starting point, we found that miR-223 can suppress glial precursor proliferation via repression of NFIA during chick spinal cord development. This relationship is conserved in glioma, as miR-223 and NFIA expression is negatively correlated in human glioma tumors, and the miR-223/NFIA axis suppresses tumorigenesis in a human glioma cell line. Subsequent analysis of NFIA function revealed that it directly represses p21 and is required for tumorigenesis in a mouse neural stem cell model of glioma. These studies represent the first characterization of miR-223/NFIA axis function in glioma and demonstrate that it is a conserved proliferative mechanism across CNS development and tumorigenesis.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Chick Embryo
  • Chromatin Immunoprecipitation
  • Gene Expression Regulation, Neoplastic / physiology
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NFI Transcription Factors / genetics
  • NFI Transcription Factors / metabolism*
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Array Analysis
  • Xenograft Model Antitumor Assays

Substances

  • MIRN223 microRNA, human
  • MicroRNAs
  • NFI Transcription Factors