MicroRNA-27a Inhibits Cell Migration and Invasion of Fibroblast-Like Synoviocytes by Targeting Follistatin-Like Protein 1 in Rheumatoid Arthritis.
MicroRNA-27a Inhibits Cell Migration and Invasion of Fibroblast-Like Synoviocytes by Targeting Follistatin-Like Protein 1 in Rheumatoid Arthritis.
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DOI：
10.14348/molcells.2016.0103
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发表时间：
2016-08-31
影响因子：
3.8
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Shi DL;Shi GR;Xie J;Du XZ;Yang H
成纤维细胞样滑膜细胞(FLS)具有异常表达的microRNA(MiRNA)，是类风湿关节炎(RA)的重要致病调节因子。先前的研究发现，在关节炎模型中，miRNA的过度表达或沉默可以促进基于miRNA的治疗方法的发展。本研究探讨miR-27A对体外培养的RA患者FLS细胞迁移和侵袭的影响。我们发现miR-27A在RA患者的血清、滑膜组织和FLS中显著下调。同时，卵泡抑素样蛋白1(FSTL1)的表达上调，提示FSTL1在类风湿关节炎的发生发展中起关键作用。Transwell实验结果表明miR-27A抑制FLS的迁移和侵袭。然而，miR-27A抑制促进了FLS的迁移和侵袭。定量逆转录-聚合酶链式反应和免疫印迹分析检测miR-27A作用后RA-FLS中基质金属蛋白酶(MMP2、MMP9和MMP13)和Rho家族蛋白(rac1、cdc42和RhoA)的表达下调。然后，荧光素酶报告实验证实miR-27A靶向FSTL1的3-非翻译区(3‘-UTR)。此外，miR-27A可显著降低FSTL1的表达。此外，miR-27A抑制TLR4和NFκB的表达，而FSTL1过表达则促进其表达。综上所述，我们发现miR-27A通过靶向FSTL1和抑制TLR4/NFκB途径来抑制RA-FLS的细胞迁移和侵袭。
Fibroblast-like synoviocytes (FLS) with aberrant expression of microRNA (miRNA) are critical pathogenic regulators in rheumatoid arthritis (RA). Previous studies have found that overexpression or silencing of miRNA can contribute to the development of miRNA-based therapeutics in arthritis models. In this study, we explored the effects of miR-27a on cell migration and invasion in cultured FLS from RA patients. We found that miR-27a was markedly downregulated in the serum, synovial tissue, and FLS of RA patients. Meanwhile, the expression of follistatin-like protein 1 (FSTL1) was upregulated, which suggests that FSTL1 plays a key role in RA development. The results of a Transwell assay showed that miR-27a inhibited FLS migration and invasion. However, miR-27a inhibition promoted the migration and invasion of FLS. In addition, the down-regulated expression of matrix metalloproteinases (MMP2, MMP9, and MMP13) and Rho family proteins (Rac1, Cdc42, and RhoA) was detected after treatment with miR-27a in RA-FLS by quantitative reverse transcription-PCR and western blot analysis. Then, a luciferase reporter assay validated that miR-27a targeted the 3-untranslated region (3′-UTR) of FSTL1. Moreover, miR-27a caused a significant decrease of FSTL1. In addition, the expression of TLR4 and NFκB was inhibited by miR-27a but increased by FSTL1 overexpression. In conclusion, we found that miR-27a inhibited cell migration and invasion of RA-FLS by targeting FSTL1 and restraining the TLR4/NFκB pathway.