Abstract
Rapidly accumulating evidence has now suggested that the long non-coding RNAs (LncRNAs), a large and diverse class of non-coding transcribed RNA molecules with diverse functional roles and mechanisms, play a major role in the pathogenesis of many human inflammatory diseases. Although some LncRNAs are overexpressed in plasma, T cell, and synovial tissues of patients with rheumatoid arthritis (RA), there is a dearth of knowledge in what role these transcripts play in fibroblast-like synoviocytes (FLSs) of these patients. Here, our studies showed that GAPLINC, a newly identified functional LncRNA in oncology, displayed a greater degree of expression in FLSs from RA than in patients with traumatic injury. GAPLINC suppression in RA-FLS cells revealed significant alterations in cell proliferation, invasion, migration, and proinflammatory cytokines production. Additionally, we performed a preliminary bioinformatics analysis of GAPLINC gene sequence in order to find its target molecules, using miRanda, PITA, RNAhybrid algorithms, Kyoto encyclopedia of genes and genomes, and gene ontology analysis. Since the results predicted that some of microRNAs and mRNA may interact with GAPLINC, we simulated a gene co-action network model based on a competitive endogenous RNA theory. Further verification of this model demonstrated that silencing of GAPLINC increased miR-382-5p and miR-575 expression. The results of this study suggest that GAPLINC may function as a novel microRNAs sponging agent affecting the biological characteristics of RA-FLSs. Additionally, GAPLINC may also promote RA-FLS tumor-like behaviors in a miR-382-5p-dependent and miR-575-dependent manner. Based upon these findings, LncRNA GAPLINC may provide a novel valuable therapeutic target for RA patients.
Highlights
Rheumatoid arthritis (RA) is one of the most chronic debilitating inflammatory autoimmune diseases characterized by synovitis and progressive destruction of joint cartilage and bone damage [1, 2]
The results showed that compared to the negative control (NC-small interference RNAs (siRNAs)) group, GAPINC silencing by siRNA-461 for 24 h led to significant decrease of mRNA expression by (84.85 ± 3.32)% (P < 0.05) (Figure 1H)
The results revealed that GAPLINC knockdown significantly reduced IL-6 (P < 0.01), IL-8 (P < 0.05), and matrix metalloproteinases-9 (MMP-9) (P < 0.05) production of rheumatoid arthritis (RA)-fibroblast-like synoviocytes (FLSs) when compared to the NC-siRNA control group (Figure S1 in Supplementary Material)
Summary
Rheumatoid arthritis (RA) is one of the most chronic debilitating inflammatory autoimmune diseases characterized by synovitis and progressive destruction of joint cartilage and bone damage [1, 2]. The FLSs are the main effector cells responsible for initiating and driving both the inflammatory process as well as the invasive nature of rheumatoid synovium [4,5,6,7]. A congeries of evidence suggests that the RA-FLSs, when activated in a chronic inflammatory environment, display many features of tumor cells. In due course, these cells eventually escape the growth limitations of contact inhibition, enhance migration, and acquire invasive ability, features essential in the pathogenesis of RA [8, 9]
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