AB0080 A SYSTEM-LEVEL APPROACH IDENTIFIES A CRITICAL REGULATOR OF CHONDROSARCOMA PROGRESSION

Background: Circular RNAs (circRNAs) participate in the initiation and progression of various diseases by miRNA sponges including postmenopausal osteoporosis[1], bladder cancer[2], and osteoarthritis (OA)[3]. However, the activity of circRNAs as “miRNA sponges” in rheumatoid arthritis (RA) has not been studied. Objectives: To investigate whether circRNA acts as competing endogenous RNA to regulate pathological processes of RA, and whether the N6-methyladenosine (m6A) modification affects Circ_0088194 stability in RA fibroblast-like synoviocytes (RA-FLSs). Methods: CircRNA microarray analysis was conducted to characterize the expression profiles of circRNAs in 3 RA-FLSs and 3 osteoarthritis fibroblast-like synoviocytes (OA-FLSs). Methylated RNA immunoprecipitation was performed to validate the level of m6A modification on Circ_0088194 in RA-FLSs and OA-FLSs. Dual-luciferase reporter assay, bioinformatics analysis, protein array analysis, and fluorescence in situ hybridization were employed to evaluate the interaction between Circ_0088194 and miR-766-3p, and between target miR-766-3p and matrix metalloproteinase 2 (MMP2). Results: Overexpression of Circ_0088194 promoted the migration and invasion of RA-FLSs and increased MMP2 expression. The expression and function of miR-766-3p were inversely correlated with Circ_0088194, which sponged miR-766-3p to upregulate MMP2 expression. Although m6A modification of Circ_0088194 exists in RA-FLSs and OA-FLSs, their level did not differ. Conclusion: This study presents an important role of this novel circRNA as a sponge of miR-766-3p to promote RA-FLS migration and invasion by targeting MMP2. However, the modification might not affect Circ_0088194 stability in RA-FLSs and OA-FLSs. Therefore, Circ_0088194 may contribute to RA development and represent as an auspicious therapeutic target. References: [1]Yu, L., and Liu, Y. (2019). circRNA_0016624 could sponge miR-98 to regulate BMP2 expression in postmenopausal osteoporosis. Biochem Biophys Res Commun 516: 546-550. [2]Yang, C., et al. (2018). Circular RNA circ-ITCH inhibits bladder cancer progression by sponging miR-17/miR-224 and regulating p21, PTEN expression. MOL CANCER 17. [3]Shen, S., et al. (2019). CircSERPINE2 protects against osteoarthritis by targeting miR-1271 and ETS-related gene. ANN RHEUM DIS 78: 826-836. Disclosure of Interests: None declared