ZEB1 represses biogenesis of circ-DOCK5 to facilitate metastasis in esophageal squamous cell carcinoma via a positive feedback loop with TGF-β

ZEB1 is an important transcription factor that plays a critical role in TGF-beta-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. However, the mechanisms by which ZEB1 regulates metastasis in esophageal squamous cell carcinoma (ESCC) remain largely unknown. Here, we identified a novel circular RNA, circ-DOCK5, the biogenesis of which is directly regulated by ZEB1 and ZEB1-repressed RNA-binding protein eIF4A3. Tissue microarray analysis identified circ-DOCK5 to be downregulated in ESCC tissues, and its down regulation correlated with poor prognosis. Moreover, circ-DOCK5 increased the stability of miR-627-3p by functioning as a reservoir for miR-627-3p to partially reverse the ZEB1-enhanced migration and invasion in ESCC. MiR-627-3p inhibited the expression of TGFB2 and the secretion of TGF-beta, which further resulted in downregulation of ZEB1 and suppression of TGF-beta-induced EMT. In vivo experiments showed that ZEB1 promoted metastasis in ESCC by regulating expression of circ-DOCK5. Therefore, the present study revealed that ZEB1-mediated downregulation of circ-DOCK5 facilitates metastasis in ESCC by forming a positive feedback loop with TGF-beta by altering the miR-627-3p/TGFB2 signaling. Targeting this signaling pathway may help suppress progression in ESCC.

Automated summary

ZEB1 mediates the downregulation of circ-DOCK5 to promote metastasis in ESCC by altering the miR-627-3p/TGFB2 signaling pathway. Targeting this signaling pathway may provide a new direction for TGF-beta targeted therapy in ESCC.