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J Neurooncol. 2018 Jun;138(2):241-250. doi: 10.1007/s11060-018-2799-3. Epub 2018 Feb 16.

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas.

Author information

1
Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St Suite 12D, Baltimore, MD, 21201, USA.
2
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
3
Department of Surgery, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD, 21201, USA.
4
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, UMB BioPark One Room 320, 800 West Baltimore St, Baltimore, MD, 21201, USA.
5
Department of Neuropathology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, 85013, USA.
6
Department of Pathology, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD, 21201, USA.
7
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St, Baltimore, MD, 21201, USA.
8
Departments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
9
Department of Surgery, University of Maryland School of Medicine, 22 S. Greene St, Baltimore, MD, 21201, USA. jwinkles@som.umaryland.edu.
10
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, UMB BioPark One Room 320, 800 West Baltimore St, Baltimore, MD, 21201, USA. jwinkles@som.umaryland.edu.
11
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St, Baltimore, MD, 21201, USA. jwinkles@som.umaryland.edu.

Abstract

The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2'-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

KEYWORDS:

DNA methylation; Fn14; Glioblastoma; IDH; TWEAK; Tumor subtypes

PMID:
29453678
PMCID:
PMC6047063
DOI:
10.1007/s11060-018-2799-3
[Indexed for MEDLINE]
Free PMC Article

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