Circular RNA CircCDKN2B−AS_006 Promotes the Tumor-like Growth and Metastasis of Rheumatoid Arthritis Synovial Fibroblasts by Targeting the miR−1258/RUNX1 Axis

Abstract

Rheumatoid arthritis (RA) is an autoimmune polyarthritis in which synovial fibroblasts (SFs) play a major role in cartilage and bone destruction through tumor−like proliferation, migration, and invasion. Circular RNAs (circRNAs) have emerged as vital regulators for tumor progression. However, the regulatory role, clinical significance, and underlying mechanisms of circRNAs in RASF tumor−like growth and metastasis remain largely unknown. Differentially expressed circRNAs in synovium samples from patients with RA and patients with joint trauma were identified via RNA sequencing. Subsequently, in vitro and in vivo experiments were performed to investigate the functional roles of circCDKN2B−AS_006 in RASF proliferation, migration, and invasion. CircCDKN2B−AS_006 was upregulated in synovium samples from patients with RA and promoted the tumor-like proliferation, migration, and invasion of RASFs. Mechanistically, circCDKN2B−AS_006 was shown to regulate the expression of runt−related transcription factor 1 (RUNX1) by sponging miR-1258, influencing the Wnt/β−catenin signaling pathway, and promoting the epithelial−to−mesenchymal transition (EMT) in RASFs. Moreover, in the collagen−induced arthritis (CIA) mouse model, intra−articular injection of lentivirus−shcircCDKN2B−AS_006 was capable of alleviating the severity of arthritis and inhibiting the aggressive behaviors of SFs. Furthermore, the correlation analysis results revealed that the circCDKN2B−AS_006/miR−1258/RUNX1 axis in the synovium was correlated with the clinical indicators of RA patients. CircCDKN2B−AS_006 promoted the proliferation, migration, and invasion of RASFs by modulating the miR−1258/RUNX1 axis.

Involvement of Epithelial-Mesenchymal Transition (EMT) in Autoimmune Diseases

“…There are consistent data indicating that the conjuncture of genetic predisposal, environmental insults, and hormonal disequilibrium may lead to the activation of the resting epithelium, the upregulation of toll-like receptors (TLRs) such as TLR-2, 3, 4, 7, 8, and 9 [182][183][184][185], leading to the release of alarmins and pro-inflammatory cytokines such as interferon (IFN), TNF-α, IL-6 and IL-17 further promoting downstream autoimmune inflammation [184,186], ultimately resulting in the atrophy and fibrosis of the salivary glands (SG) (Figure 4) [187,188]. Over the past 15 years, several lines of evidence seem to indicate that RA-FLSs may, at least in part, undergo EMT-like process (Table 1) [31,170,171]. This conclusion was indeed supported by immunohistological analysis of both healthy and RA synovium that showed the presence of α-SMA, a myofibroblast marker responsible for collagen accumulation in fibrosis exclusively in the synovial lining layer of RA patients [31,171,172].…”

“…A pre-clinical study on CIA rats confirmed the role of circCDKN2B−AS_006 in the proliferative and invasive phenotype of RA-FLSs, whereas its knockdown alleviated the severity of arthritis. Mechanistic analysis concluded that circCDKN2B−AS_006 promoted EMT-like processes in RA-FLSs by inducing the expression of runt-related transcription factor 1 (Runx1), ultimately activating the Wnt/β−catenin signaling pathway (Table 1) [170]. sion of runt-related transcription factor 1 (Runx1), ultimately activating the Wnt/β−catenin signaling pathway (Table 1) [170].…”

“…Mechanistic analysis concluded that circCDKN2B−AS_006 promoted EMT-like processes in RA-FLSs by inducing the expression of runt-related transcription factor 1 (Runx1), ultimately activating the Wnt/β−catenin signaling pathway (Table 1) [170]. sion of runt-related transcription factor 1 (Runx1), ultimately activating the Wnt/β−catenin signaling pathway (Table 1) [170]. biopsies from RA patients.…”

“…A pre-clinical study on CIA rats confirmed the role of circCDKN2B−AS_006 in the proliferative and invasive phenotype of RA-FLSs, whereas its knockdown alleviated the severity of arthritis. Mechanistic analysis concluded that circCDKN2B−AS_006 promoted EMT-like processes in RA-FLSs by inducing the expression of runt-related transcription factor 1 (Runx1), ultimately activating the Wnt/β−catenin signaling pathway (Table 1) [170]. Abbreviations: AKT: protein kinase B; α-SMA: α-smooth muscle actin; CIA: collagen-induced arthritis; EMT: epithelial-mesenchymal transition; HIF1α: hypoxia-inducible factor 1α; IL: interleukin; MMPs: matrix metalloproteases; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor-κB; PI3K: phosphoinositide 3-kinase; RA: rheumatoid arthritis; RA-FLSs: RA fibroblast-like synoviocytes; Ref.…”

“…HIF-α invasion, resistance to apoptosis [176] Snai1 invasion [178] Runx1 invasion [170] in kinase B; α-SMA: α-smooth muscle actin; CIA: collagen-induced arsenchymal transition; HIF1α: hypoxia-inducible factor 1α; IL: interleukin; eases; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor-κB; kinase; RA: rheumatoid arthritis; RA-FLSs: RA fibroblast-like synovio-X1: runt-related transcription factor 1; SMAD: homolog of the Drosophst decapentaplegic (Mad) and the Caenorhabditis elegans protein Sma; scriptional Repressor 1; TFs: transcription factors; TGF-β: transforming or necrosis factor; ⇧: upregulated; ⇩: downregulated .…”