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Journal of Neuro-Oncology

, Volume 138, Issue 2, pp 241–250 | Cite as

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

  • David S. Hersh
  • Sen Peng
  • Jimena G. Dancy
  • Rebeca Galisteo
  • Jennifer M. Eschbacher
  • Rudy J. Castellani
  • Jonathan E. Heath
  • Teklu Legesse
  • Anthony J. Kim
  • Graeme F. Woodworth
  • Nhan L. Tran
  • Jeffrey A. WinklesEmail author
Laboratory Investigation

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

TWEAK Fn14 IDH Glioblastoma Tumor subtypes DNA methylation 

Notes

Acknowledgements

We thank Dr. Craig Horbinski for providing the glioma cell lines. We also thank Ashley Cellini and Kimberly Tuttle for their assistance with obtaining tissue slides from the University of Maryland Greenebaum Cancer Center’s Pathology and Biorepository Shared Service. This work was supported in part by National Institutes of Health Grant K08 NS09043 (G.F.W.), American Cancer Society Research Scholar Grant 128970-RSG-16-012-01-CDD (G.F.W.), and The Ben and Catherine Ivy Foundation (N.L.T.). J.G.D. was supported by the NIH T32 Training Grant CA154274 and an NIGMS Initiative for Maximizing Student Development Grant (R25 GM55036).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving tissue from human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Given that this tissue was obtained from a tumor bank retrospectively, the institutional review board determined that formal consent is not required.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • David S. Hersh
    • 1
  • Sen Peng
    • 2
  • Jimena G. Dancy
    • 1
  • Rebeca Galisteo
    • 3
    • 4
  • Jennifer M. Eschbacher
    • 5
  • Rudy J. Castellani
    • 6
  • Jonathan E. Heath
    • 6
  • Teklu Legesse
    • 6
  • Anthony J. Kim
    • 1
    • 7
  • Graeme F. Woodworth
    • 1
    • 7
  • Nhan L. Tran
    • 8
  • Jeffrey A. Winkles
    • 3
    • 4
    • 7
    Email author
  1. 1.Department of NeurosurgeryUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Cancer and Cell Biology DivisionTranslational Genomics Research InstitutePhoenixUSA
  3. 3.Department of SurgeryUniversity of Maryland School of MedicineBaltimoreUSA
  4. 4.Center for Vascular and Inflammatory DiseasesUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Department of Neuropathology, Barrow Neurological InstituteSt. Joseph’s Hospital and Medical CenterPhoenixUSA
  6. 6.Department of PathologyUniversity of Maryland School of MedicineBaltimoreUSA
  7. 7.University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer CenterBaltimoreUSA
  8. 8.Departments of Cancer Biology and NeurosurgeryMayo Clinic ArizonaScottsdaleUSA

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