TY - JOUR AU - Luedi, M.M. AU - Singh, S.K. AU - Mosley, J.C. AU - Hatami, M. AU - Gumin, J. AU - Sulman, E.P. AU - Lang, F.F. AU - Stueber, F. AU - Zinn, P.O. AU - Colen, R.R. PY - 2017// TI - A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients T2 - J Neurosurg Anesthesiol JO - Journal of Neurosurgical Anesthesiology SP - 46 EP - 58 VL - 29 IS - 1 KW - Animals KW - Antineoplastic Agents KW - Hormonal/*pharmacology KW - Apoptosis KW - Blotting KW - Western KW - Brain Neoplasms/*mortality KW - Cell Line KW - Tumor KW - Cell Survival KW - Dexamethasone/*pharmacology KW - Flow Cytometry KW - Gene Expression Regulation KW - Neoplastic/*drug effects KW - Glioblastoma/*mortality KW - Humans KW - Mice KW - Prognosis KW - Stem Cells/drug effects KW - Survival Analysis AB - BACKGROUND: Dexamethasone is reported to induce both tumor-suppressive and tumor-promoting effects. The purpose of this study was to identify the genomic impact of dexamethasone in glioblastoma stem cell (GSC) lines and its prognostic value; furthermore, to identify drugs that can counter these side effects of dexamethasone exposure. METHODS: We utilized 3 independent GSC lines with tumorigenic potential for this study. Whole-genome expression profiling and pathway analyses were done with dexamethasone-exposed and control cells. GSCs were also co-exposed to dexamethasone and temozolomide. Risk scores were calculated for most affected genes, and their associations with survival in The Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data databases. In silico Connectivity Map analysis identified camptothecin as antagonist to dexamethasone-induced negative effects. RESULTS: Pathway analyses predicted an activation of dexamethasone network (z-score: 2.908). Top activated canonical pathways included "role of breast cancer 1 in DNA damage response" (P=1.07E-04). GSCs were protected against temozolomide-induced apoptosis when coincubated with dexamethasone. Altered cellular functions included cell movement, cell survival, and apoptosis with z-scores of 2.815, 5.137, and -3.122, respectively. CCAAT/enhancer binding protein beta (CEBPB) was activated in a dose dependent manner specifically in slow-dividing "stem-like" cells. CEBPB was activated in dexamethasone-treated orthotopic tumors. Patients with high risk scores had significantly shorter survival. Camptothecin was validated as potential partial neutralizer of dexamethasone-induced oncogenic effects. CONCLUSIONS: Dexamethasone exposure induces a genetic program and CEBPB expression in GSCs that adversely affects key cellular functions and response to therapeutics. High risk scores associated with these genes have negative prognostic value in patients. Our findings further suggest camptothecin as a potential neutralizer of adverse dexamethasone-mediated effects. SN - 0898-4921 UR - http://www.ncbi.nlm.nih.gov/pubmed/27653222 UR - PM:27653222 N1 - PMID:27653222 ID - Luedi_etal2017 ER -