EGF-induced C/EBPβ participates in EMT by decreasing the expression of miR-203 in esophageal squamous cell carcinoma cells

Junxia Li, Fabo Shan, Gang Xiong, Xuedan Chen, Xingying Guan, Ju-Ming Wang, Wen-Lin Wang, Xueqing Xu, Yun Bai
Journal of Cell Science 2014 September 1, 127 (Pt 17): 3735-44
Epithelial-mesenchymal transition (EMT) is a developmental program that is associated with esophageal squamous cell carcinoma (ESCC) progression and metastasis. Recently, C/EBPβ 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 β (C/EBPβ) LIP isoform is abnormally overexpressed and correlated with cancer metastasis in clinical specimens of human ESCC. Furthermore, we demonstrate that C/EBPβ 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/EBPβ LIP. Disruption of C/EBPβ LIP attenuated the EGF-mediated decrease in miR-203, whereas overexpression of C/EBPβ LIP alone markedly suppressed miR-203. In addition, we demonstrated that C/EBPβ 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/EBPβ-LIP-mediated downregulation of miR-203, which plays a key role in EMT and metastasis.

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