1051

CEBPB

epithelial-mesenchymal transition (EMT) is a developmental program that is associated with esophageal squamous cell carcinoma (ESCC) progression and metastasis. Recently, C/EBPbeta has been reported to be an EMT inducer in cancer. However, the detailed molecular mechanisms remain unclear. Here, we report for the first time, that the truncated CCAAT-enhancer-binding protein beta (C/EBPbeta) LIP isoform is abnormally overexpressed and correlated with cancer metastasis in clinical specimens of human ESCC. Furthermore, we demonstrate that C/EBPbeta LIP mediates epithelial growth factor (EGF)-induced EMT and increases migration and invasion of esophageal cancer cells in a manner that is dependent on miR-203 inactivation. Finally, we identified miR-203 as a direct target of C/EBPbeta LIP. Disruption of C/EBPbeta LIP attenuated the EGF-mediated decrease in miR-203, whereas overexpression of C/EBPbeta LIP alone markedly suppressed miR-203. In addition, we demonstrated that C/EBPbeta LIP inhibited miR-203 transcription by directly interacting with a conserved distal regulatory element upstream of the miR-203 locus, and in doing so, orchestrated chromatin remodeling. In conclusion, our results have revealed a new regulatory mechanism that involves C/EBPbeta-LIP-mediated downregulation of miR-203, which plays a key role in EMT and metastasis.CI - (c) 2014. Published by The Company of Biologists Ltd.

The microRNA miR-17-92 cluster plays a fundamental role in heart development. The aim of this study was to investigate the effect of a member of this cluster, miR-17, on cardiac senescence. We examined the roles of miR-17 in senescence and demonstrated that miR-17-3p attenuates cardiac aging in the myocardium by targeting Par4 (also known as PAWR). This upregulates the downstream proteins CEBPB, FAK, N-cadherin, vimentin, Oct4 and Sca-1 (also known as stem cell antigen-1), and downregulates E-cadherin. Par4 has been reported as a tumor suppressor gene that induces apoptosis in cancer cells, but not in normal cells. Repression of Par4 by miR-17-3p enhances the transcription of CEBPB and FAK, which promotes mouse cardiac fibroblast (MCF) epithelial-to-mesenchymal transition (EMT) and self-renewal, resulting in cellular senescence and apoptosis resistance. We conclude that Par4 can bind to the CEBPB promoter and inhibit its transcription. Decreased Par4 expression increases the amount of CEBPB, which binds to the FAK promoter and enhances FAK transcription. Par4, CEBPB and FAK form a senescence signaling pathway, playing roles in modulating cell survival, growth, apoptosis, EMT and self-renewal. Through this novel senescence signaling axis, miR-17-3p represses Par4 expression, acting pleiotropically as a negative modulator of cardiac aging and cardiac fibroblast cellular senescence.CI - (c) 2015. Published by The Company of Biologists Ltd.