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

Article

关键词: EPIDERMAL-GROWTH-FACTOR;    BINDING-PROTEIN-BETA;    TRANSCRIPTIONAL INHIBITORY PROTEIN;    NF-KAPPA-B;    FACTOR RECEPTOR;    GENE-EXPRESSION;    MESSENGER-RNA;    LIP;    ACTIVATION;    LAP;   

DOI  :  10.1096/fj.201600550R

来源: SCIE

【 摘 要 】

We investigated the intersection of epidermal growth factor receptor (EGFR) and CCAAT enhancer binding protein (C/EBP)-beta signaling in glioblastoma (GBM), given that both gene products strongly influence neoplastic behavior. C/EBP-beta is known to drive themesenchymal 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-beta expression, as well as enhanced nuclear translocation and DNA-beta inding activity, leading to upregulation of C/EBP-beta transcription and translation. Deeper investigation identified bidirectional regulation, with C/EBP-beta 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-beta [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-beta 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-beta pathway interactions uncovered a complex signaling network in which increased activity of either EGFRorC/EBP-beta leads to the up-regulation of the other, enhancing oncogenic signaling. Disrupting the EGFR-C/EBP-beta signaling axis could attenuate malignant behavior of glioblastoma.

【 授权许可】

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