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Cancers (Basel). 2019 Jan 4;11(1). pii: E41. doi: 10.3390/cancers11010041.

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

Author information

1
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. s.berendsen-2@umcutrecht.nl.
2
Department of Pathology, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. W.G.M.Spliet@umcutrecht.nl.
3
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. M.Geurts-2@umcutrecht.nl.
4
Department of Pathology, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. w.vanhecke@umcutrecht.nl.
5
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. t.seute@umcutrecht.nl.
6
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. T.J.Snijders@umcutrecht.nl.
7
Department of Human Genetics, GIGA Research Center, University of Liège, Avenue de l Hôpital, 1, 4000 Liège, Belgium. vbours@uliege.be.
8
Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital, The Ohio State University, West 10th Avenue, Columbus, OH 43210, USA. Erica.Bell@osumc.edu.
9
Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital, The Ohio State University, West 10th Avenue, Columbus, OH 43210, USA. Arnab.Chakravarti@osumc.edu.
10
Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. p.robe@umcutrecht.nl.
11
Department of Human Genetics, GIGA Research Center, University of Liège, Avenue de l Hôpital, 1, 4000 Liège, Belgium. p.robe@umcutrecht.nl.
12
Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital, The Ohio State University, West 10th Avenue, Columbus, OH 43210, USA. p.robe@umcutrecht.nl.

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.

KEYWORDS:

GSEA; HIF-1α; STAT5b; epilepsy; glioblastoma; hypoxia; mesenchymal transformation; tissue microarrays; translational research

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