The mechanism of circ-ARAP2 regulation of tumor EMT and stem cell differentiation affecting proliferation, invasion and chemotherapy resistance of Esophageal Squamous Cell Carcinoma

Circular RNAs (circRNAs) belong to a novel class of noncoding RNA that gained more attention in human cancer pathogenesis. The circRNA roles in esophageal squamous cell carcinoma (ESCC) is unknown. Present investigation was to characterize new circRNAs regulating ESCC progression and explore the regulatory mechanisms in ESCC. In this study, circRNAs differentially expressed in ESCC and adjacent normal tissues were characterized via high-throughput sequencing. We then investigated the effects of the differentially expressed circRNA ARFGAP with RhoGAP domain, ankyrin repeat and PH domain 2 (circ-ARAP2) on tumor progression in vivo and in vitro. We used luciferase reporter assays to identify the relationships between circ-ARAP2, its target microRNA (miR)-761 and the cell cycle regulator Forkhead Box M1 (FOXM1). Expression profile analyses regarding human circRNAs in ESCC demonstrated that circ-ARAP2 was up-regulated significantly in ESCC tissues and cell lines. The circ-ARAP2 down-regulation suppressed ESCC proliferation, tumor growth and metastasis in vivo and in vitro. The data also suggested that miR-761 and FOXM1 were circ-ARAP2 downstream targets which were confirmed through luciferase reporter analysis. Overexpression of FOXM1 or inhibiting miR-761 slowed ESCC cell proliferation and invasion after silencing circ-ARAP2. circ-ARAP2 also influenced the endothelial-mesenchymal transition (EMT) and cancer stem cells differently by regulating miR-761/FOXM1. In one word, the results demonstrated that abnormal circ-ARAP2 expression promoted ESCC progression by regulating miR-761/FOXM1 axis-mediated stemness and EMT.