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Nat Commun. 2016 Jul 29;7:12329. doi: 10.1038/ncomms12329.

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

Author information

1
Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.
2
Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
3
Focus Program Translational Neurosciences (FTN), University of Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany.
4
Department of Neuropathology, Heinrich Heine University of Düsseldorf, Düsseldorf and German Cancer Consortium (DKTK), Moorenstr. 5, 40225 partner site Essen/Düsseldorf, Germany.
5
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
6
Max Planck Institute for Brain Research, Max-von-Laue Str. 4, 60438 Frankfurt, Germany.

Abstract

Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.

PMID:
27470974
PMCID:
PMC4974575
DOI:
10.1038/ncomms12329
[Indexed for MEDLINE]
Free PMC Article

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