Epilepsy Associates with Decreased HIF-1α/STAT5b Signaling in Glioblastoma.

Sharon Berendsen,Wim G M Spliet,Pierre A Robe,Vincent Bours,Arnab Chakravarti,Marjolein Geurts,Tatjana Seute,Tom J Snijders,Erica H Bell,Wim Van Hecke

doi:10.3390/cancers11010041

Abstract

Epilepsy at presentation is an independent favorable prognostic factor in glioblastoma (GBM). In this study, we analyze the oncologic signaling pathways that associate with epilepsy in human GBMs, and that can underlie this prognostic effect. Following ethical approval and patient consent, fresh frozen GBM tissue was obtained from 76 patient surgeries. Hospital records were screened for the presence of seizures at presentation of the disease. mRNA and miRNA expression-based and gene set enrichment analyses were performed on these tissues, to uncover candidate oncologic pathways that associate with epilepsy. We performed qPCR experiments and immunohistochemistry on tissue microarrays containing 286 GBMs to further explore the association of these candidate pathways and of markers of mesenchymal transformation (NF-κB, CEBP-β, STAT3, STAT5b, VEGFA, SRF) with epilepsy. Gene sets involved in hypoxia/HIF-1α, STAT5, CEBP-β and epithelial-mesenchymal transformation signaling were significantly downregulated in epileptogenic GBMs. On confirmatory protein expression analyses, epileptogenic tumors were characterized by a significant downregulation of phospho-STAT5b, a target of HIF-1α. Epilepsy status did not associate with molecular subclassification or miRNA expression patterns of the tumors. Epileptogenic GBMs correlate with decreased hypoxia/ HIF-1α/STAT5b signaling compared to glioblastomas that do not present with epilepsy.

Highlights

Glioblastoma (GBM) is the most malignant primary brain tumor with a dismal prognosis
The disease presents itself with epileptic seizures in 30–40% of the cases [6,7], and we previously showed that epilepsy at presentation is an independent favorable prognostic factor for overall survival in glioblastoma patients [7]
30 presented with epilepsy and 46 had different symptoms at presentation of the disease. mRNA expression analysis was performed for 73 patients, after quality control and removal of three outliers. miRNA expression analysis was performed for 72 patients, as four samples were removed due to insufficient RNA quality

Summary

Introduction

Glioblastoma (GBM) is the most malignant primary brain tumor with a dismal prognosis. The disease presents itself with epileptic seizures in 30–40% of the cases [6,7], and we previously showed that epilepsy at presentation is an independent favorable prognostic factor for overall survival in glioblastoma patients [7]. This prognostic effect could not be explained by treatment with specific anti-epileptic drugs [7,8], a smaller tumor volume at presentation, due to an earlier detection of the tumor, or IDH1 mutations [7]. The mechanisms underlying this prognostic effect in glioblastoma remain to be elucidated

Methods

Results

Conclusion