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Erschienen in: Journal of Neuro-Oncology 1/2016

27.08.2016 | Laboratory Investigation

ZEB1 expression is increased in IDH1-mutant lower-grade gliomas

verfasst von: Cody L. Nesvick, Chao Zhang, Nancy A. Edwards, Blake K. Montgomery, Michaela Lee, Chunzhang Yang, Herui Wang, Dongwang Zhu, John D. Heiss, Marsha J. Merrill, Abhik Ray-Chaudhury, Zhengping Zhuang

Erschienen in: Journal of Neuro-Oncology | Ausgabe 1/2016

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Abstract

Transcription factors that induce epithelial-mesenchymal transition (EMT) promote invasion, chemoresistance and a stem-cell phenotype in epithelial tumors, but their roles in central nervous system tumors are not well-understood. We hypothesized these transcription factors have a functional impact in grades II–III gliomas. Using the National Cancer Institute (NCI) Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the Cancer Genome Atlas (TCGA) Lower-Grade Glioma (LGG) data, we determined the impact of EMT-promoting transcription factors (EMT-TFs) on overall survival in grades II–III gliomas, compared their expression across common genetic subtypes and subsequently validated these findings in a set of 31 tumors using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Increased expression of the gene coding for the transcriptional repressor Zinc Finger E box-binding Homeobox 1 (ZEB1) was associated with a significant increase in overall survival (OS) on Kaplan–Meier analysis. Genetic subtype analysis revealed that ZEB1 expression was relatively increased in IDH1/2-mutant gliomas, and IDH1/2-mutant gliomas expressed significantly lower levels of many ZEB1 transcriptional targets. Similarly, IDH1/2-mutant tumors expressed significantly higher levels of targets of microRNA 200C (MIR200C), a key regulator of ZEB1. In a validation study, ZEB1 mRNA was significantly increased in IDH1-mutant grades II–III gliomas, and ZEB1 protein expression was more pronounced in these tumors. Our findings demonstrate a novel relationship between IDH1/2 mutations and expression of ZEB1 and its transcriptional targets. Therapy targeting ZEB1-associated pathways may represent a novel therapeutic avenue for this class of tumors.
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Metadaten
Titel
ZEB1 expression is increased in IDH1-mutant lower-grade gliomas
verfasst von
Cody L. Nesvick
Chao Zhang
Nancy A. Edwards
Blake K. Montgomery
Michaela Lee
Chunzhang Yang
Herui Wang
Dongwang Zhu
John D. Heiss
Marsha J. Merrill
Abhik Ray-Chaudhury
Zhengping Zhuang
Publikationsdatum
27.08.2016
Verlag
Springer US
Erschienen in
Journal of Neuro-Oncology / Ausgabe 1/2016
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-016-2240-8

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