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槲皮素通过调控miR-431-5p/鼠双微基因4信号通路抑制类风湿关节炎成纤维样滑膜细胞侵袭和促进凋亡

Quercetin inhibits invasion and promotes apoptosis of rheumatoid arthritis fibroblast-like synoviocytes by regulating miR-431-5p/mouse double minute 4 signaling pathway

    摘要
  • 摘要:
    目的 探讨槲皮素对类风湿关节炎成纤维样滑膜细胞(RA-FLSs)侵袭和凋亡的影响以及分子机制。
    方法 收集27例RA患者和25例非RA患者的滑膜组织。分析miR-431-5p和鼠双微基因4(MDM4) mRNA表达及其蛋白表达。将miR-431-5p抑制剂、miR-NC、MDM4过表达载体和pcDNA 3.1(+)载体转染至RA-FLSs, 转染后48 h, 在每孔中添加槲皮素，并收集细胞，测定细胞活力、细胞凋亡率和侵袭细胞数。采用双荧光素酶实验分析miR-431-5p和MDM4的结合关系。
    结果 miR-431-5p在RA滑膜组织和RA-FLSs中表达下调，在槲皮素诱导的RA-FLSs中上调，差异有统计学意义(P < 0.05)。miR-431-5p低表达或者MDM4过表达减弱了槲皮素对RA-FLSs凋亡的促进作用及对侵袭的抑制作用(P < 0.05)。miR-431-5p在RA-FLSs中结合MDM4, 且miR-431-5p通过MDM4调控RA-FLSs的凋亡和侵袭(P < 0.05)。
    结论 槲皮素通过介导miR-431-5p/MDM4信号通路来调控RA-FLSs侵袭和凋亡，提示槲皮素可能是治疗RA的替代药物。

     

    Abstract:
    Objective To investigate the effect of quercetin on invasion and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and its molecular mechanism.
    Methods Synovial tissues of 27 patients with RA and 25 patients without RA were collected. The mRNA expression and protein expression of miR-431-5p and mouse double minute 4 (MDM4) were analyzed. MiR-431-5p inhibitor, miR-NC, MDM4 overexpression vector and pcDNA 3.1 (+) vector were transfected into RA-FLSs. At 48 h after transfection, quercetin was added to each well, and cells were collected and cell viability, apoptosis rate and number of invasive cells were measured. Dual luciferase assay was used to analyze the binding relationship between miR-431-5p and MDM4.
    Results The expression of miR-431-5p was significantly down-regulated in RA synovial tissue and RA-FLSs, and significantly up-regulated in quercetin induced RA-FLSS (P < 0.05). The low expression of miR-431-5p or the overexpression of MDM4 weakened the promoting effect of quercetin on apoptosis of RA-FLSs and the inhibiting effect on invasion (P < 0.05). MiR-431-5p binded MDM4 in RA-FLSs, and miR-431-5p regulated apoptosis and invasion of RA-FLSs through MDM4 (P < 0.05).
    Conclusion Quercetin regulates the invasion and apoptosis of RA-FLSS by mediating miR-431-5p/MDM4 signaling pathway, suggesting that quercetin may be an alternative drug for RA.

     

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