LncRNA PICSAR promotes cell proliferation, migration and invasion of fibroblast-like synoviocytes by sponging miRNA-4701-5p in rheumatoid arthritis

Abstract

BackgroundLong non-coding RNAs (lncRNAs) have drawn increasing attention because they play a pivotal role in various types of autoimmune diseases, including rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLSs), a prominent component of hyperplastic synovial pannus tissue, are the primary effector cells in RA synovial hyperplasia and invasion which can lead to joint destruction. In this study, we investigated whether lncRNAs could act as competing endogenous RNAs to regulate the pathological behaviors of RA-FLSs.MethodsLncRNA microarray was conducted to establish lncRNA expression profiles in FLSs isolated from RA patients and healthy controls (HCs). Differentially expressed lncRNAs were verified by quantitative real-time PCR (qRT-PCR) on RA-FLSs and synovial fluid. The functional role of lncRNA PICSAR downregulation was evaluated in RA-FLSs. We conducted molecular biological analysis to predict miRNAs which have a potential binding site for PICSAR and further refined the results by qRT-PCR. Luciferase reporter assay was adopted to validate the interaction of lncRNA PICSAR and miR-4701-5p. Western Blot and qPCR were used to identify the target gene and protein. The functional role of miR-4701-5p upregulation was examined in RA-FLSs.FindingsWe identified a long intergenic non-protein-coding RNA162 (LINC00162), also known as lncRNA PICSAR (p38 inhibited cutaneous squamous cell carcinoma associated lincRNA), has significantly higher expression in RA-FLSs and RA synovial fluid. The cell proliferation, migration, invasion and proinflammatory cytokines production of RA-FLSs showed significant alterations after the lncRNA PICSAR suppression. Mechanistically, lncRNA PICSAR functioned through sponging miR-4701-5p in RA-FLSs.InterpretationOur results reveal PICSAR may exert an essential role in promoting synovial invasion and joint destruction by sponging miR-4701-5p in RA and that lncRNA PICSAR may act as a biomarker of RA.

Epigenetic Regulation Mediated by miRNA in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

“…In addition to produce RANKL, fibroblast-like synoviocytes in RA (C) also activates osteoclast differentiation by producing inflammatory cytokines, chemokines and matrix metalloproteinases (MMPs) (60). Large number evidence showed down-regulation of miR-22 (61), miR-29c-3p (62), miR-124a (63), miR-4701-5p (8), and upregultion of miR-143 (64), miR-145 (64) and miR-191 (65) increased the proliferation, migration and invasion of RA-FLS. In contrast, down-regulation of miR-132-3p (62), miR-29a (37) and up-regulation of miR-31-5p (62) and miR-124a (66) inhibited the proliferation, migration and invasion of RA-FLS (62).…”

Epigenetic Regulation Mediated by microRNAs in the Susceptibility and Pathogenesis of Rheumatoid Arthritis

“…In addition to producing RANKL, fibroblast-like synoviocytes in RA (RA-FLS) also activate osteoclast differentiation by releasing inflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs) (Rana et al, 2018). Ample evidence shows that downregulation of miR-22 (Lin et al, 2014), miR-29c-3p (Tseng et al, 2019), miR-124a (Nakamachi et al, 2009), and miR-4701-5p (Bi et al, 2019), and up-regulation of miR-143 (Hong et al, 2017), miR-145 (Hong et al, 2017), and miR-191 (Yu et al, 2019) enhances the proliferation, migration, and invasion of RA-FLS. In contrast, down-regulation of miR-132-3p (Tseng et al, 2019) and miR-29a , and up-regulation of miR-31-5p (Tseng et al, 2019) and miR-124a (Meng et al, 2020) inhibits these processes (Tseng et al, 2019).…”

“…In view of the current therapy strategies and treatment frames, early accurate diagnosis, effective and personalized treatment, and precision medicine have become increasingly urgent for RA patients. A comprehensive understanding of RA is hence required, from the angles of both genetics (HLA and non-HLA variants) (Okada et al, 2014) epigenetics (DNA methylation Chen et al, 2019;Guo et al, 2020b), microRNA (Furer et al, 2010;Mizoguchi and Kohsaka, 2012), lncRNA (Bi et al, 2019;Guo et al, 2019), and histone modifications (Angiolilli et al, 2017)).…”

Editorial: Immunomodulatory Functions of Fibroblast-like Synoviocytes in Joint Inflammation and Destruction during Rheumatoid Arthritis

“…Rheumatoid Arthritis (RA) is a common rheumatic disorder characterized by persistent synovial inflammation and destruction of joints. Fibroblast-like synoviocytes (FLSs) exhibit critical immunomodulatory functions through secretion of inflammatory cytokines and through direct interactions with several synovial-infiltrated immune cell types (1,2). RA FLSs also display surprisingly aggressive behavior (3), metabolic changes (4,5), and epigenetic alterations (6,7).…”