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MicroRNA-146a inhibits glioma development by targeting Notch1

Jie Mei1, Robert Bachoo, Chun-Li Zhang

  • 1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.

Molecular and Cellular Biology
|July 7, 2011
PubMed

Insights

MicroRNA-146a (miR-146a) suppresses glioma growth by inhibiting Notch1 signaling. This microRNA acts as a negative feedback mechanism, offering potential new brain tumor treatment strategies.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Gliomagenesis is driven by dysregulated epidermal growth factor receptor (EGFR) signaling, INK4A/ARF, and PTEN inactivation.
  • EGFR activation and PTEN inactivation induce microRNA-146a (miR-146a) expression.

Purpose of the Study:

  • To investigate the role of miR-146a in gliomagenesis.
  • To elucidate the molecular mechanisms by which miR-146a affects glioma development and neural stem cells.

Main Methods:

  • Global microRNA expression analysis.
  • Overexpression and knockdown studies of miR-146a in murine astrocytes and human glioblastoma cell lines.
  • Orthotopic xenograft models.
  • Analysis of Notch1 as a direct target of miR-146a.

Main Results:

  • Overexpression of miR-146a attenuated proliferation, migration, and tumorigenicity in astrocytes and inhibited glioma development in vivo.
  • miR-146a functions by downregulating Notch1, a key regulator of neural stem cell maintenance.
  • miR-146a modulated neural stem cell proliferation and differentiation, reducing glioma stem-like cell formation and migration.
  • Knockdown of miR-146a promoted astrocyte tumorigenesis via Notch1 upregulation.

Conclusions:

  • miR-146a is induced by oncogenic cues as a negative-feedback mechanism to restrict tumor growth by repressing Notch1.
  • miR-146a plays a critical role in linking neural stem cell pathways to gliomagenesis.
  • These findings suggest miR-146a as a potential therapeutic target for brain tumors.

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