title: EGFR and C/EBP-β oncogenic signaling is bidirectional in human glioma and varies with the C/EBP-β isoform.
abstract: We investigated the intersection of epidermal growth factor receptor (EGFR) and CCAAT enhancer binding protein (C/EBP)-β signaling in glioblastoma (GBM), given that both gene products strongly influence neoplastic behavior. C/EBP-β is known to drive the mesenchymal transcriptional signature in GBM, likely through strong microenvironmental influences, whereas the genetic contributions to its up-regulation in this disease are not well described. We demonstrated that stable overexpression and activation of WT EGFR (U87MG-WT) led to elevated C/EBP-β expression, as well as enhanced nuclear translocation and DNA-binding activity, leading to up-regulation of C/EBP-β transcription and translation. Deeper investigation identified bidirectional regulation, with C/EBP-β also causing up-regulation of EGFR that was at least partially dependent on the STAT3. Based on ChIP-based studies, we also found that that the translational isoforms of C/EBP-β [liver-enriched transcription-activating protein (LAP)-1/2 and liver inhibitory protein (LIP)] have differential occupancy on STAT3 promoter and opposing roles in transcriptional regulation of STAT3 and EGFR. We further demonstrated that the shorter C/EBP-β isoform, LIP, promoted proliferation and migration of U87MG glioma cells, potentially via induction of cytokine IL-6. Our molecular dissection of EGFR and C/EBP-β pathway interactions uncovered a complex signaling network in which increased activity of either EGFR or C/EBP-β leads to the up-regulation of the other, enhancing oncogenic signaling. Disrupting the EGFR-C/EBP-β signaling axis could attenuate malignant behavior of glioblastoma.-Selagea, L., Mishra, A., Anand, M., Ross, J., Tucker-Burden, C., Kong, J., Brat, D. J. EGFR and C/EBP-β oncogenic signaling is bidirectional in human glioma and varies with the C/EBP-β isoform.
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.|Department of Biology, Agnes Scott College, Decatur, Georgia.
authors: Ligia
authors: L
authors: Selagea
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors: Alok
authors: A
authors: Mishra
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors: Monika
authors: M
authors: Anand
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.|Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, Georgia; and.
authors: James
authors: J
authors: Ross
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia.
authors: Carol
authors: C
authors: Tucker-Burden
authors: Department of Biomedical Informatics, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors: Jun
authors: J
authors: Kong
authors: Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia; dbrat@emory.edu.|Department of Biomedical Informatics, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors: Daniel J
authors: DJ
authors: Brat
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000502:physiology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D020033:Protein Isoforms; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: LAP; LIP; cell signaling; glioblastoma