Abstract
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.
Highlights
Gastric cancer (GC) is one of the epidemic tumors of the digestive system in China and in the world.[1]
The heatmap of top 20 up and downregulated circRNAs shown in (Figure 1A), and we found that circREPS2 is one of the most significant downregulated circRNAs in GC
Fluorescence in situ hybridization (FISH) analysis revealed that circREPS2 was predominantly located in the cytoplasm of BGC-823 cells and SGC-7901(Figure 1G)
Summary
Gastric cancer (GC) is one of the epidemic tumors of the digestive system in China and in the world.[1]. Circular RNAs (circRNAs), comprising a relatively large family of noncoding RNAs, originate from noncanonical splicing events called back-splicing.[5,6] circRNAs have become ideal biomarkers for multiple tumors and have been shown to exert suitable potential therapeutic effects on cancers.[7] To date, most circRNAs have been identified and proposed to act as microRNA (miRNA) sponges.[8] Cdr1as is a wellknown circRNA that contains more than seventy binding sites and serves as a sponge for miRNA-7 in neuronal tissues.[8] circRNAs can function through related proteins. CircRNAs are involved in multiple disease types and play roles in gene expression, proliferation, apoptosis, autophagy, EMT, etc.[11] a large number of circRNAs in GC are still unknown, and further studies are needed to understand their functional mechanisms
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