Annexin A2–STAT3–Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma
Open Access
- 5 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica Communications
- Vol. 8 (1), 1-13
- https://doi.org/10.1186/s40478-020-00916-7
Abstract
Glioblastoma (GBM) is characterized by extensive tumor cell invasion, angiogenesis, and proliferation. We previously established subclones of GBM cells with distinct invasive phenotypes and identified annexin A2 (ANXA2) as an activator of angiogenesis and perivascular invasion. Here, we further explored the role of ANXA2 in regulating phenotypic transition in GBM. We identified oncostatin M receptor (OSMR) as a key ANXA2 target gene in GBM utilizing microarray analysis and hierarchical clustering analysis of the Ivy Glioblastoma Atlas Project and The Cancer Genome Atlas datasets. Overexpression of ANXA2 in GBM cells increased the expression of OSMR and phosphorylated signal transducer and activator of transcription 3 (STAT3) and enhanced cell invasion, angiogenesis, proliferation, and mesenchymal transition. Silencing of OSMR reversed the ANXA2-induced phenotype, and STAT3 knockdown reduced OSMR protein expression. Exposure of GBM cells to hypoxic conditions activated the ANXA2–STAT3–OSMR signaling axis. Mice bearing ANXA2-overexpressing GBM exhibited shorter survival times compared with control tumor-bearing mice, whereas OSMR knockdown increased the survival time and diminished ANXA2-mediated tumor invasion, angiogenesis, and growth. Further, we uncovered a significant relationship between ANXA2 and OSMR expression in clinical GBM specimens, and demonstrated their correlation with tumor histopathology and patient prognosis. Our results indicate that the ANXA2–STAT3–OSMR axis regulates malignant phenotypic changes and mesenchymal transition in GBM, suggesting that this axis is a promising therapeutic target to treat GBM aggressiveness.Funding Information
- Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17K10866, 17K10865)
This publication has 45 references indexed in Scilit:
- Proteomics‐based analysis of invasion‐related proteins in malignant gliomasNeuropathology, 2012
- Maintenance of primary tumor phenotype and genotype in glioblastoma stem cellsNeuro-Oncology, 2011
- Activated STAT3 Regulates Hypoxia-Induced Angiogenesis and Cell Migration in Human GlioblastomaNeurosurgery, 2010
- Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1Cancer Cell, 2010
- Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1Nature, 2009
- Sphingosine-1-Phosphate Regulates Glioblastoma Cell Invasiveness through the Urokinase Plasminogen Activator System and CCN1/Cyr61Molecular Cancer Research, 2009
- Oncostatin-M induction of vascular endothelial growth factor expression in astroglioma cellsOncogene, 2003
- Potentiated Gene Delivery to Tumors Using Herpes Simplex Virus/Epstein-Barr Virus/RV Tribrid Amplicon VectorsHuman Gene Therapy, 2003
- Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesisNature, 1992
- A CRITICAL REVIEW: THE PATHOLOGY OF CEREBRAL GLIOMASJournal of Neurology, Neurosurgery & Psychiatry, 1940