ABSTRACT
Long noncoding RNAs (lncRNAs) are specifically expressed in different diseases and regulate disease progression. To explore the functions of rheumatoid arthritis (RA)-specific lncRNA, we determined the lncRNA expression profile of fibroblast-like synoviocytes (FLS) obtained from patients with RA and osteoarthritis (OA) using a LncRNA microarray and identified up-regulated LncNFYB in RA as a potential therapeutic target. Using gain- and loss-of-function studies, LncNFYB was proven to promote FLS proliferation and cell cycle progress but not affect their invasion, migration, and apoptotic abilities. Further investigation discovered that LncRNA could combine with annexin A2 (ANXA2) and enhance the level of phospho-ANXA2 (Tyr24) in the plasma membrane area, which induced the activation of ERK1/2 to promote proliferation. These findings provide new insights into the biological functions of LncNFYB on modification of FLS, which may be exploited for the therapy of RA.
Subject(s)
Annexin A2 , Arthritis, Rheumatoid , MAP Kinase Signaling System , RNA, Long Noncoding , Synoviocytes , Humans , Annexin A2/genetics , Annexin A2/metabolism , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/physiopathology , Cell Proliferation/genetics , Cells, Cultured , Enzyme Activation/genetics , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Expression Profiling , Osteoarthritis/genetics , Osteoarthritis/metabolism , Osteoarthritis/physiopathology , Phosphorylation/genetics , Protein Binding/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Synoviocytes/cytology , Synoviocytes/metabolismABSTRACT
OBJECTIVE: The study aimed to explore the effect of serum uric acid (SUA) level on the progression of kidney function in systemic lupus erythematosus (SLE) patients. METHODS: A total of 123 biopsy-proven lupus nephritis (LN) patients were included in this retrospective observational study. Cox proportional hazard regression analyses as well as restricted cubic spline analyses were performed to identify predictors of renal outcome in LN patients. We also performed a systematic review and meta-analysis for SUA and overall kidney outcomes in SLE patients. RESULTS: Based on the laboratory tests at renal biopsy, 72 (58.5%) of the 123 patients had hyperuricemia. The median (IQR) follow-up duration was 3.67 years (1.79-6.63 years), and a total of 110 (89.4%) patients experienced progression of LN. Increased serum uric acid level, whether analyzed as continuous or categorical variable, was associated with higher risk of LN progression in Cox proportional hazard regression model (hazard ratio [HR]: 1.003, 95% confidence interval [CI]: 1.001-1.005; HR: 1.780, 95% CI: 1.201-2.639, respectively). This relationship maintained in women (HR: 1.947, 95% CI: 1.234-3.074) but not men (HR: 2.189, 95% CI: 0.802-5.977). The meta-analysis showed a similar result that both continuous and categorical SUA were positively associated with the risk of kidney function progression in LN (weighted mean difference [WMD]: 1.73, 95% CI: 0.97-2.49; odds ratio [OR]: 1.55, 95% CI: 1.20-2.01, respectively). CONCLUSIONS: Our study found overall and especially in women that higher SUA in LN patients were associated with increased risk of renal progression. Meta-analysis yielded consistent results. Future studies are required to establish if uric acid can be used as a biomarker for risk assessment and/or as a novel therapeutic target in SLE.
Subject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Female , Humans , East Asian People , Kidney/pathology , Lupus Nephritis/complications , Retrospective Studies , Uric AcidABSTRACT
Super enhancer (SE) is a cluster of enhancers that has a stronger ability to promote transcription compared to the typical enhancer (TE). Similar to TE, which can transcribe enhancer RNA (eRNA), SE produces super enhancer RNA (seRNA). The activation of SE is cell and tissue-specific, and the SE-associated genes are mostly linked to the cell fate. This is demonstrated by the important role-played by SE in the embryonic stem cell (ESC) and multiple cancer development. SeRNA regulates transcription in both cis and trans configuration, and those located in the cytoplasm mediates various cell activities. However, the functions of seRNAs are unclear, and most of them have a synergistic effect with SE and SE-associated genes. In this mini review, we summarized the mechanisms of seRNA and functions of both SE and seRNA.
Subject(s)
Enhancer Elements, Genetic , RNA, Untranslated/genetics , Animals , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Humans , RNA, Untranslated/metabolismABSTRACT
Dysregulation of circular RNAs (circRNAs) is involved in various human diseases. Fibroblast-like synoviocytes (FLSs), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype and contribute to joint destruction in rheumatoid arthritis (RA). In the present study, we identified a novel circRNA, Circ_0088194, which was upregulated in RA fibroblast-like synoviocytes (RA-FLSs) and correlated with the disease activity score in 28 joints. Overexpression of Circ_0088194 promoted RA-FLS migration and invasion, while inhibition of Circ_0088194 had the opposite effect. Mechanistically, Circ_0088194 acted as a miR-766-3p sponge to relieve the repressive effect of miR-766-3p on its target, MMP2 (encoding matrix metalloproteinase 2), thereby promoting migration and invasion. The expression level of Circ_0088194 was inversely correlated with that of miR-766-3p in RA-FLSs. Importantly, overexpression of miR-766-3p partially blocked the migration and invasion induced by Circ_0088194 overexpression. Collectively, this study identified a novel circRNA Circ_0088194 that promotes RA-FLS invasion and migration via the miR-766-3p/MMP2 axis. Circ_0088194 might represent a novel therapeutic target to prevent and treat RA.