Identification and Characterization of Circular RNAs as a New Class of Putative Biomarkers in Diabetes Retinopathy

PURPOSE. To reveal the expression profile and clinical significance of circular RNAs (circRNAs) in diabetic retinopathy (DR). METHODS. Circular RNA microarrays were performed to identify DR-related circRNAs. Gene ontology (GO) enrichment and KEGG analysis was performed to determine the biologic modules and signaling pathway. TargetScan and miRana program was used to predict circRNA/miRNA interaction. Quantitative PCR assays were performed to detect circRNA expression pattern in clinical samples. Ki67 staining, Transwell, tube formation, and spheroid sprouting assays were performed to investigate the role and mechanism of circRNA in endothelial angiogenic function. RESULTS. A total of 529 circRNAs were aberrantly expressed in diabetic retinas. The host genes of differentially expressed circRNAs were targeted to ATP binding (biologic process); extracellular exosome (cellular component); and intracellular signal transduction (molecular function). Circ 0005015 was verified to be upregulated in the plasma, vitreous sample, and fibrovascular membranes of DR patients. Circ_0005015 facilitated retinal endothelial angiogenic function via regulating endothelial cell proliferation, migration, and tube formation. Circ 0005015 acted as miR-519d-3p sponge to inhibit miR-519d-3p activity, leading to increased MMP-2, XIAP, and STAT3 expression. CONCLUSIONS. circRNAs are involved in DR pathogenesis, and thus serve as potential biomarkers of DR diagnosis.