ZEB1 expression is increased in IDH1-mutant lower-grade gliomas.
J Neurooncol
; 130(1): 111-122, 2016 10.
Article
in En
| MEDLINE
| ID: mdl-27568035
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
Gene Expression Regulation, Neoplastic
/
Zinc Finger E-box-Binding Homeobox 1
/
Glioma
/
Isocitrate Dehydrogenase
/
Mutation
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
J Neurooncol
Year:
2016
Type:
Article
Affiliation country:
United States