BACKGROUND Long 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. METHODS LncRNA 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. FINDINGS We 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. INTERPRETATION Our 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.

中文翻译：

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LncRNA PICSAR通过使类风湿关节炎中的miRNA-4701-5p海绵化，促进细胞增殖，迁移和侵袭成纤维细胞样滑膜细胞。

背景技术长的非编码RNA（lncRNA）已引起越来越多的关注，因为它们在包括风湿性关节炎（RA）在内的各种类型的自身免疫性疾病中起着举足轻重的作用。成纤维样滑膜细胞（FLSs）是增生性滑膜血管pan组织的重要组成部分，是RA滑膜增生和侵袭的主要效应细胞，可导致关节破坏。在这项研究中，我们调查了lncRNA是否可以作为竞争性内源性RNA来调节RA-FLS的病理行为。方法采用LncRNA微阵列技术建立从RA患者和健康人（HCs）中分离出的FLS中lncRNA的表达谱。通过在RA-FLS和滑液上的实时定量PCR（qRT-PCR）验证了差异表达的lncRNA。在RA-FLS中评估了lncRNA PICSAR下调的功能作用。我们进行了分子生物学分析，以预测具有与PICSAR潜在结合位点的miRNA，并通过qRT-PCR进一步完善结果。采用荧光素酶报告基因检测法验证lncRNA PICSAR和miR-4701-5p的相互作用。Western Blot和qPCR用于鉴定目标基因和蛋白质。在RA-FLS中检查了miR-4701-5p上调的功能。研究结果我们确定了一个长的基因间非蛋白质编码RNA162（LINC00162），也称为lncRNA PICSAR（p38抑制了皮肤鳞状细胞癌相关的lincRNA），在RA-FLS和RA滑液中的表达明显较高。细胞增殖，迁移，lncRNA PICSAR抑制后，RA-FLS的侵袭和促炎细胞因子的产生显示出明显的变化。从机制上讲，lncRNA PICSAR通过使miR-4701-5p在RA-FLS中起海绵作用。解释我们的结果表明，PICSAR可能通过在RA中海绵化miR-4701-5p在促进滑膜侵袭和关节破坏中起重要作用，而lncRNA PICSAR可能充当RA的生物标记。