The transcription factor PPARα is overexpressed and is associated with a favourable prognosis in IDH-wildtype primary glioblastoma

Singleton, William G.B.; Haynes, Harry R.; White, Paul; Hares, Kelly M.; Redondo, Juliana; Kemp, Kevin C.; Singleton, WGB; Killick-Cole, Clare L.; Stevens, Jonathan R.; Garadi, Krishnakumar; Guglani, Sam; Wilkins, Alastair; Kurian, Kathreena M.

Abstract

© 2016 John Wiley & Sons Ltd Aims: PPARα agonists are in current clinical use as hypolipidaemic agents and show significant antineoplastic effects in human glioblastoma models. To date however, the expression of PPARα in large-scale glioblastoma datasets has not been examined. We aimed to investigate the expression of the transcription factor PPARα in primary glioblastoma, the relationship between PPARα expression and patients’ clinicopathological features and other molecular markers associated with gliomagenesis. Methods and results: With protein immunoblotting techniques and reverse transcription quantitative real-time PCR, PPARα was found to be significantly overexpressed in glioblastoma compared with control brain tissue (P = 0.032 and P = 0.005). PPARA gene expression was found to be enriched in the classical glioblastoma subtype within The Cancer Genome Atlas (TCGA) dataset. Although not associated with overall survival when assessed by immunohistochemistry, cross-validation with the TCGA dataset and multivariate analyses identified PPARA gene expression as an independent prognostic marker for overall survival (P = 0.042). Finally, hierarchical clustering revealed novel, significant associations between high PPARA expression and a putative set of glioblastoma molecular mediators including EMX2, AQP4, and NTRK2. Conclusions: PPARα is overexpressed in primary glioblastoma and high PPARA expression functions as an independent prognostic marker in the glioblastoma TCGA dataset. Further studies are required to explore genetic associations with high PPARA expression and to analyse the predictive role of PPARα expression in glioblastoma models in response to PPARα agonists.

• Journal Article Type: Article
• Acceptance Date: Nov 29, 2016
• Online Publication Date: Dec 7, 2016
• Publication Date: Jun 1, 2017
• Deposit Date: Dec 6, 2016
• Publicly Available Date: Dec 7, 2017
• Journal: Histopathology
• Print ISSN: 0309-0167
• Electronic ISSN: 1365-2559
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 70
• Issue: 7
• Pages: 1030-1043
• DOI: https://doi.org/10.1111/his.13142
• Keywords: PPARalpha, glioblastoma
• Public URL: https://uwe-repository.worktribe.com/output/885259
• Publisher URL: http://dx.doi.org/10.1111/his.13142
• Additional Information: Additional Information : This is the peer reviewed version of the following article: Haynes, H., White, P., Hares, K., Redondo, J., Kemp, K., Singleton, W., Killick-Cole, C., Stevens, J., Garadi, K., Guglani, S., Wilkins, A. and Kurian, K. (2017) The transcription factor PPARalpha is overexpressed and is associated with a favourable prognosis in IDH-wildtype primary glioblastoma. Histopathology, 70 (7). pp. 1030-1043. ISSN 0309-0167 Available from: http://eprints.uwe.ac.uk/30531, which has been published in final form at http://dx.doi.org/10.1111/his.13142. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
• Contract Date: Dec 6, 2016