Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth

• Published in: Scientific reports Vol. 10; no. 1; p. 5504
• Main Authors: Leventoux, N., Augustus, M., Azar, S., Riquier, S., Villemin, J. P., Guelfi, S., Falha, L., Bauchet, L., Gozé, C., Ritchie, W., Commes, T., Duffau, H., Rigau, V. , Hugnot, J. P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-03-2020; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/51; 13/89; 14/19; 38/61; 631/67; 631/67/1922; Astrocytes; Biochemistry, Molecular Biology; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Cancer; Carbon-Oxygen Lyases - genetics; Cell interactions; Cell Line, Tumor; Cell Proliferation; Cell signaling; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Connexin 43; Cytoskeleton; Disease Progression; Down-Regulation; Enzymes; Epidermal growth factor receptors; Ethanolamine; Ethanolamine-phosphate phospho-lyase; Gap junctions; Gene Expression Profiling; Genetic transformation; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma cells; Humanities and Social Sciences; Humans; Immunohistochemistry; Isocitrate Dehydrogenase - genetics; Life Sciences; Lipid Metabolism; Localization; Metabolism; multidisciplinary; Mutation; Neural coding; Neurobiology; Neurons and Cognition; Phosphorylation; Protein biosynthesis; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Signal Transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; Stem cells; Tumors; Wnt protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-62145-1

IDH1-mutated gliomas are slow-growing brain tumours which progress into high-grade gliomas. The early molecular events causing this progression are ill-defined. Previous studies revealed that 20% of these tumours already have transformation foci. These foci offer opportunities to better understand malignant progression. We used immunohistochemistry and high throughput RNA profiling to characterize foci cells. These have higher pSTAT3 staining revealing activation of JAK/STAT signaling. They downregulate RNAs involved in Wnt signaling (
DAAM2, SFRP2
), EGFR signaling (
MLC1
), cytoskeleton and cell-cell communication (
EZR, GJA1
). In addition, foci cells show reduced levels of RNA coding for Ethanolamine-Phosphate Phospho-Lyase (
ETNPPL/AGXT2L1
), a lipid metabolism enzyme. ETNPPL is involved in the catabolism of phosphoethanolamine implicated in membrane synthesis. We detected ETNPPL protein in glioma cells as well as in astrocytes in the human brain. Its nuclear localization suggests additional roles for this enzyme.
ETNPPL
expression is inversely correlated to glioma grade and we found no ETNPPL protein in glioblastomas. Overexpression of ETNPPL reduces the growth of glioma stem cells indicating that this enzyme opposes gliomagenesis. Collectively, these results suggest that a combined alteration in membrane lipid metabolism and STAT3 pathway promotes IDH1-mutated glioma malignant progression.