Dataset Information

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

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-?B, CEBP-?, STAT3, STAT5b, VEGFA, SRF) with epilepsy. Gene sets involved in hypoxia/HIF-1?, STAT5, CEBP-? 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-1?. Epilepsy status did not associate with molecular subclassification or miRNA expression patterns of the tumors. Epileptogenic GBMs correlate with decreased hypoxia/ HIF-1?/STAT5b signaling compared to glioblastomas that do not present with epilepsy.

SUBMITTER: Berendsen S

PROVIDER: S-EPMC6356242 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Berendsen Sharon S Spliet Wim G M WGM Geurts Marjolein M Van Hecke Wim W Seute Tatjana T Snijders Tom J TJ Bours Vincent V Bell Erica H EH Chakravarti Arnab A Robe Pierre A PA

Cancers 20190104 1

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 enrichme ...[more]

PMID: 30621209

Similar Datasets

Project description:BackgroundCancer cells undergo cellular adaptation through metabolic reprogramming to sustain survival and rapid growth under various stress conditions. However, how brain tumors modulate their metabolic flexibility in the naturally serine/glycine (S/G)-deficient brain microenvironment remain unknown.MethodsWe used a range of primary/stem-like and established glioblastoma (GBM) cell models in vitro and in vivo. To identify the regulatory mechanisms of S/G deprivation-induced metabolic flexibility, we employed high-throughput RNA-sequencing, transcriptomic analysis, metabolic flux analysis, metabolites analysis, chromatin immunoprecipitation (ChIP), luciferase reporter, nuclear fractionation, cycloheximide-chase, and glucose consumption. The clinical significances were analyzed in the genomic database (GSE4290) and in human GBM specimens.ResultsThe high-throughput RNA-sequencing and transcriptomic analysis demonstrate that the de novo serine synthesis pathway (SSP) and glycolysis are highly activated in GBM cells under S/G deprivation conditions. Mechanistically, S/G deprivation rapidly induces reactive oxygen species (ROS)-mediated AMP-activated protein kinase (AMPK) activation and AMPK-dependent hypoxia-inducible factor (HIF)-1α stabilization and transactivation. Activated HIF-1α in turn promotes the expression of SSP enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). In addition, the HIF-1α-induced expression of glycolytic genes (GLUT1, GLUT3, HK2, and PFKFB2) promotes glucose uptake, glycolysis, and glycolytic flux to fuel SSP, leading to elevated de novo serine and glycine biosynthesis, NADPH/NADP+ ratio, and the proliferation and survival of GBM cells. Analyses of human GBM specimens reveal that the levels of overexpressed PHGDH, PSAT1, and PSPH are positively correlated with levels of AMPK T172 phosphorylation and HIF-1α expression and the poor prognosis of GBM patients.ConclusionOur findings reveal that metabolic stress-enhanced glucose-derived de novo serine biosynthesis is a critical metabolic feature of GBM cells, and highlight the potential to target SSP for treating human GBM.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets