EGFR and C/EBP-β oncogenic signaling is bidirectional in human glioma and varies with the C/EBP-β isoform

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 inh...