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EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance

C Depner1, H Zum Buttel2, N Böğürcü1

  • 1Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.

Nature Communications
|July 30, 2016
PubMed

Insights

Glioma invasion is promoted by downregulation of ephrinB2, a gene silenced by epigenetic changes and hypoxia-induced ZEB2. Targeting ZEB2 can inhibit glioma invasion and overcome resistance to anti-angiogenic therapies.

Area of Science:

  • Neuro-oncology
  • Molecular biology
  • Cancer genetics

Background:

  • Diffuse invasion of brain parenchyma is a significant challenge in glioma treatment.
  • Anti-angiogenic agents face limitations due to tumor invasion and resistance mechanisms.

Purpose of the Study:

  • To identify key molecular mechanisms driving glioma invasion.
  • To investigate the role of ephrinB2 in glioma progression and therapeutic resistance.

Main Methods:

  • Analysis of ephrinB2 expression in human gliomas.
  • Genetic manipulation of ephrinB2 in a murine glioma model.
  • Investigation of hypoxia-inducible factor (HIF)-1α and ZEB2 involvement.
  • Assessment of ZEB2 inhibition in blocking tumor invasion.

Main Results:

  • EphrinB2 is downregulated in human gliomas via promoter hypermethylation and gene deletion.
  • Genetic deletion of ephrinB2 exacerbates invasion in a mouse glioma model.
  • Hypoxia-induced HIF-1α upregulates ZEB2, which represses ephrinB2 expression, enhancing invasiveness.
  • This mechanism is activated by anti-angiogenic treatment and blocked by ZEB2 inhibition.

Conclusions:

  • EphrinB2 downregulation is a critical step promoting glioma invasion.
  • ZEB2 acts as a key mediator of hypoxia-induced invasion and therapeutic resistance.
  • Targeting ZEB2 presents a promising strategy to inhibit glioma invasion and improve treatment outcomes.

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