环状RNA-104871/miR-140-3p/SIRT1轴促进RA滑膜成纤维细胞增殖迁移的机制研究

Our study identified that the expression of circRNA_104871 were both upregulated in RA fibroblast-like synoviocytes (FLS) and peripheral blood mononuclear cell compared to controls. Overexpression of circRNA_104871 could enhance the proliferation and migration of RA FLS, however, the mechanism was unknown yet. We found that circRNA_104871 sequence contained a binding site of miR-140-3p by bioinformatics analysis. In our study, we found that the expression of miR-140-3p was significantly lower in RA FLS than osteoarthritis FLS, and overexpression of circRNA_104871 could diminish miR-140-3p expression, which demonstrated that circRNA_104871 may functions as a competitive endogenous RNA to sponge miR-140-3p. Study showed that the expression of silent information regulator 1(SIRT1) were increased in RA FLS than OA FLS and overexpression of SIRT1 could accelerate the proliferation and migration of RA FLS. Research showed that SIRT1 was a direct target of miRNA-140-3p. Thus, we suggested that circRNA_104871 may function as a competitive endogenous RNA to promote the proliferation and migration of FLS by regulating SIRT1 expression through sponging miR-140-3p in RA. The elucidation of the mechanism can provide new target for the development of RA drugs.

实验发现circRNA_104871在RA滑膜成纤维细胞（FLS）和外周血单个核细胞中均表达升高。在RA FLS中过表达circRNA_104871，FLS增殖迁移能力增加，但机制未明。生物信息学分析发现circRNA_104871有miR-140-3p结合位点，实验发现miR-140-3p在RA FLS中表达降低。在RA FLS中过表达circRNA_104871，miR-140-3p表达下降，说明circRNA_104871可能通过吸附miR-140-3p起作用。研究表明沉默信息调节因子1（SIRT1）在RA FLS表达升高并可促进RA FLS增殖迁移，且有研究者在软骨细胞中证明了SIRT1是miR-140-3p一个直接靶基因。因此我们推测circRNA_104871可能通过吸附miR-140-3p调控SIRT1促进RA FLS增殖迁移。该机制的阐明可为RA治疗药物的研发提供新思路。

没有研究报道环状RNA在类风湿关节炎（RA）中的作用。试验发现circ_104871在RA滑膜成纤维细胞（FLS）和外周血单个核细胞中表达升高，在RAFLS中过表达circ_104871,FLS增殖迁移能力增加，但其机制未明。生物信息学分析发现circ_104871序列上有miR-140-3p结合位点，试验发现miR-140-3p在RA FLS表达与OA相比显著降低，在RA FLS过表达circ_104871，miR-140-3p表达下降。说明circ_104871可能通过吸附miR-140-3p起作用。研究表明沉默信息调节因子1（SIRT1）3′UTR端有miR-140-3p的结合位点，两者可直接相互作用。SIRT1在RAFLS的表达升高并可促进RAFLS增殖和迁移。因此我们推测circ_104871可能通过吸附miR-140-3p调控SIRT1促进RAFLS的增殖和迁移。.该项目实验已基本完成，circRNA_10487在circBase里的命名为circ_0088036，我们实验证明circRNA_10487(circ_0088036)以竞争性内源RNA的方式结合miR-140-3p调控SIRT1进而促进 RA滑膜成纤维细胞增殖和迁移，相关数据发表在Molecular Immunology (IF=3.641)。.另外我们通过单细胞测序检测了干燥综合征外周PBMC，探索了血CD4+细胞毒性T细胞参与自身免疫病的研究，相关文章发表在Frontiers in Immunology（IF=5.085）。.最后我们通过芯片及后续的验证实验发现一个新的circRNA—circ_0088194在RA滑膜成纤维细胞中表达升高，并且通过实验证明了circ_0088194可通过miR-776-3p/MMP轴促RA滑膜成纤维细胞迁移和侵袭，相关文章发表在Frontiers in Immunology（IF=5.085）。