Long Noncoding RNA HAFML Promotes Migration and Invasion of Rheumatoid Fibroblast-like Synoviocytes

Abstract

Abstract The aggressive phenotype exhibited by fibroblast-like synoviocytes (FLSs) is critical for the progression of joint destruction in rheumatoid arthritis (RA). Long noncoding RNAs (lncRNAs) have crucial roles in the pathogenesis of diverse disorders; however, few have been identified that might be able to control the joint damage in RA. In this study, we identified an lncRNA, ENST00000509194, which was expressed at abnormally high levels in FLSs and synovial tissues from patients with RA. ENST00000509194 positively modulates the migration and invasion of FLSs by interacting with human Ag R (HuR, also called ELAVL1), an RNA-binding protein that mainly stabilizes mRNAs. ENST00000509194 binds directly to HuR in the cytoplasm to form a complex that promotes the expression of the endocytic adaptor protein APPL2 by stabilizing APPL2 mRNA. Knockdown of HuR or APPL2 impaired the migration and invasion of RA FLSs. Given its close association with HuR and FLS migration, we named ENST00000509194 as HAFML (HuR-associated fibroblast migratory lncRNA). Our findings suggest that an increase in synovial HAFML might contribute to FLS-mediated rheumatoid synovial aggression and joint destruction, and that the lncRNA HAFML might be a potential therapeutic target for dysregulated fibroblasts in a wide range of diseases.