Circular RNA circREPS2 Acts as a Sponge of miR-558 to Suppress Gastric Cancer Progression by Regulating RUNX3/β-catenin Signaling

Circular RNAs (circRNAs) play an essential regulatory role in multiple cancers. However, the role of a large number of circRNAs in gastric cancer (GC) is still unknown. Here, hsa_circ_0139996 (circREPS2), a novel circRNA that was significantly downregulated in GC, was selected for further investigation. circREPS2 was validated and analyzed by DNA sequencing and quantitative real-time PCR. The roles of circREPS2 in GC cells were verified by gain- and loss-of-function experiments. Bioinformatics analysis, luciferase reporter, RNA pull-down, and RNA immunoprecipitation assays were performed to evaluate the functional mechanism of circREPS2 on microRNA-558 (miR-558)/RUNX3/β-catenin axis in GC cells. In the present study, we found that circREPS2 was downregulated in GC tissues and cell lines. Low expression of circREPS2 was associated with a higher tumor-node-metastasis (TNM) stage, poor tumor differentiation, and larger tumor size in GC patients. Functionally, circREPS2 significantly inhibited GC cell proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT) in vitro and tumorigenesis in vivo. Furthermore, our data demonstrated that circREPS2 acted as a miR-558 sponge and upregulated RUNX3 expression to inactivate β-catenin signaling in GC cells. In conclusion, circREPS2 suppresses the progression of GC via miR-558/RUNX3/β-catenin signaling and is a novel promising biomarker and target for GC treatment. [Display omitted] Wang and colleagues identified a novel circular RNA, circREPS2, which is dysregulated in GC. circREPS2 upregulates RUNX3 expression by sponging miR-558, leading to inhibition of β-catenin pathway transcriptional activity, thereby inhibiting GC cell proliferation, metastasis, and EMT. These observations suggest that circREPS2 may serve as a therapeutic target for GC.