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长链非编码RNA LOC100912373通过吸附miR-17-5p调节丙酮酸脱氢酶激酶1(PDK1)的表达,以促进类风湿关节炎中滑膜成纤维样细胞的增殖。

LncRNA LOC100912373 modulates PDK1 expression by sponging miR-17-5p to promote the proliferation of fibroblast-like synoviocytes in rheumatoid arthritis.

作者信息

Fan Chang, Cui Xiaoya, Chen Sen, Huang Shaopeng, Jiang Hui

机构信息

Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine Hefei, Anhui, China.

School of Pharmacy, Anhui University of Chinese Medicine Hefei, Anhui, China.

出版信息

Am J Transl Res. 2020 Dec 15;12(12):7709-7723. eCollection 2020.

Abstract

Rheumatoid arthritis (RA) is a common autoimmune disease and characterized by chronic inflammation, abnormal synovial cell proliferation, and joint swelling and tenderness, and it causes patients substantial pain. To date, the pathogenesis of RA remains unclear, and specific treatment is still lacking in the clinic. Evidence from previous research indicated that the long noncoding RNA (lncRNA) LOC100912373 is a key lncRNA and involved in RA. However, our understanding of the specific mechanism of lncRNA LOC100912373 in RA development and progression is still in its infancy. In this study, fibroblast-like synoviocytes (FLSs) were cultured by enzyme-dispersed and substrate-attached explant methods. The MTT method, flow cytometry and transmission electron microscopy were used to determine the effect of lncRNA LOC100912373 on FLSs. The expression of key genes such as lncRNA LOC100912373, miR-17-5p, PDK1 and AKT in FLSs was detected by RT-qPCR, immunofluorescence and Western blot. The localization of lncRNA LOC100912373 was determined by fluorescence in situ hybridization. The specific targeting relationship between lncRNA LOC100912373 and miR-17-5p/PDK1 was verified by RNA immunoprecipitation and luciferase reporter gene analysis. The results showed that lncRNA LOC100912373 localized in the cytoplasm and was highly expressed in the synovial tissues and FLSs of AA rats. LncRNA LOC100912373 overexpression promoted the proliferation of FLSs. In addition, lncRNA LOC100912373 could bind to miR-17-5p, and the expression of lncRNA LOC100912373 was negatively correlated with miR-17-5p and positively correlated with PDK1/AKT. In conclusion, lncRNA LOC100912373 may upregulate the expression of PDK1 by sponging miR-17-5p, accelerating the phosphorylation of AKT and inducing the proliferation of FLSs, thus promoting the occurrence and development of RA.

摘要

类风湿关节炎(RA)是一种常见的自身免疫性疾病,其特征为慢性炎症、滑膜细胞异常增殖以及关节肿胀和压痛,给患者带来极大痛苦。迄今为止,RA的发病机制仍不清楚,临床上仍缺乏特异性治疗方法。以往研究证据表明,长链非编码RNA(lncRNA)LOC100912373是一种关键lncRNA,参与RA发病过程。然而,我们对lncRNA LOC100912373在RA发生发展中具体机制的了解仍处于起步阶段。在本研究中,采用酶消化和贴壁外植体法培养成纤维样滑膜细胞(FLS)。运用MTT法、流式细胞术和透射电子显微镜检测lncRNA LOC100912373对FLS的影响。通过RT-qPCR、免疫荧光和蛋白质免疫印迹法检测FLS中lncRNA LOC100912373、miR-17-5p、PDK1和AKT等关键基因的表达。通过荧光原位杂交确定lncRNA LOC100912373的定位。通过RNA免疫沉淀和荧光素酶报告基因分析验证lncRNA LOC100912373与miR-17-5p/PDK1之间的特异性靶向关系。结果显示,lncRNA LOC100912373定位于细胞质,在佐剂性关节炎(AA)大鼠的滑膜组织和FLS中高表达。lncRNA LOC100912373过表达促进FLS增殖。此外,lncRNA LOC100912373可与miR-17-5p结合,lncRNA LOC100912373的表达与miR-17-5p呈负相关,与PDK1/AKT呈正相关。总之,lncRNA LOC100912373可能通过海绵吸附miR-17-5p上调PDK1表达,加速AKT磷酸化并诱导FLS增殖,从而促进RA的发生发展。

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