Abstract
BackgroundCirc_0000396 was found to be down-regulated in the rheumatoid arthritis (RA) patients and had a high diagnostic value. However, the function and mechanisms underlying circ_0000396 in RA progression remain unclear.MethodsThe expression of circ_0000396, microRNA (miR)-203 and HMG-box transcription factor 1 (HBP1) was detected using qRT-PCR and western blot. The proliferative and apoptotic capabilities of rheumatoid arthritis synovial fibroblasts (RASFs) were measured by colony formation, CCK-8, flow cytometry and western blot assays, respectively. The levels of interleukins (IL)-6, IL-1β, IL-8 and tumor necrosis factor-α (TNF-α) were detected using enzyme-linked immunosorbent assay (ELISA). The target correlations between miR-203 and circ_0000396 or HBP1 were validated using pull-down and dual-luciferase reporter assay.ResultsCirc_0000396 was decreased in RA synovial tissues and RASFs, and overexpression of circ_0000396 suppressed cell proliferation, induced cell apoptosis and reduced the release of inflammatory cytokine IL-6, IL-1β, IL-8 and TNF-α in RASFs, while circ_0000396 deletion functioned oppositely. MiR-203 was confirmed to be a target of circ_0000396, and miR-203 reversed the protective effects of circ_0000396 on the dysfunction and inflammation of RASFs. HBP1 was a target of miR-203, and silencing miR-203 inhibited RASFs malignant changes by regulating HBP1. In addition, circ_0000396 could regulate HBP1 by sponging miR-203, and HBP1 decrease attenuated the effects of circ_0000396 on RASF growth and inflammation.ConclusionCirc_0000396 inhibited the growth and inflammation in RASFs by regulating miR-203/HBP1 axis, providing a potential therapeutic target for RA.
Highlights
Circ_0000396 was found to be down-regulated in the rheumatoid arthritis (RA) patients and had a high diagnostic value
The results showed that circ_0000396 expression was significantly decreased in synovial tissues with RA relative to these in non-RA controls (Fig. 1a)
We found that the inhibition of miR-203 enhanced the luciferase activity of the circ_0000396 WT reporter vector but not mutant reporter vector in rheumatoid arthritis synovial fibroblasts (RASFs) (Fig. 3c)
Summary
Circ_0000396 was found to be down-regulated in the rheumatoid arthritis (RA) patients and had a high diagnostic value. The function and mechanisms underlying circ_0000396 in RA progression remain unclear. Luo et al [13] proved that hsa_circ_0044235 in peripheral blood was the potential biomarker for the diagnosis of RA patients. Li et al [15] demonstrated hsa_circ_0001859 up-regulated ATF2 through miR-204/211 to stimulate inflammation in SW982 cells. Circ_0000396 is a novel identified circRNA; it has been found that it was downregulated in the RA patients versus the healthy group, and showed a higher receiver operating characteristic (ROC) area under the curve (AUC), while circ_0000396 might be a potential diagnostic biomarker for RA patients [16]. The roles of circ_0000396 in RASF dysfunction remain unclear
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