LncRNA NEAT1_1 suppresses tumor-like biologic behaviors of fibroblast-like synoviocytes by targeting the miR-221-3p/uPAR axis in rheumatoid arthritis
LncRNA NEAT1_1 suppresses tumor-like biologic behaviors of fibroblast-like synoviocytes by targeting the miR-221-3p/uPAR axis in rheumatoid arthritis
复制标题
LncRNA NEAT1_1 通过靶向类风湿关节炎中的 miR-221-3p/uPAR 轴抑制成纤维样滑膜细胞的肿瘤样生物学行为
DOI：
10.1002/jlb.3a0121-067rrr
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发表时间：
2021
影响因子：
5.5
通讯作者：
Pan Yunfeng
中科院分区：
文献类型：
--
作者：
Wang Manli;Chen Yixiong;Bi Xuan;Luo Xiqing;Hu Zuoyu;Liu Yan;Shi Xiaoyi;Weng Weizhen;Mo Biyao;Lu Yan;Pan Yunfeng
成纤维细胞样滑膜细胞（FLS）是类风湿关节炎（RA）病理过程中的主要效应细胞。因此，阐明RA-FLS生物学行为的分子机制将有助于开发治疗RA的有效靶点。我们以前已经证明，RA-FLS的肿瘤样生物学行为是由尿激酶型纤溶酶原激活物受体（uPAR），RA-FLS中的特异性上调受体加剧。在此，我们进一步研究uPAR的作用机制，阐明其在RA-FLS中的作用。我们证明miR-221- 3 p与uPAR正相关，并调节RA-FLS中uPAR的水平。同时，一个长的非编码RNA，核旁斑装配转录本1_1（NEAT1_1），它可以预测性地靶向miR-221- 3 p在三个位点，表明在RA-FLS中的竞争性内源RNA的可能性很大。有趣的是，NEAT1_1和miR-221- 3 p可以在RA-FLS的细胞核和细胞质中共存。重要的是，NEAT1_1可以作为miR-221- 3 p/uPAR轴和下游JAK信号传导的变阻器。NEAT1_1负调控RA-FLS的肿瘤样特征和细胞因子分泌，与其生物学功能一致。总的来说，我们的数据提供了新的见解NEAT1_1在调节RA-FLS肿瘤样行为的机制。靶向NEAT1_1和miR-221- 3 p/uPAR轴可能在RA患者中具有有希望的治疗作用。
Fibroblast-like synoviocytes (FLSs) are the predominant effector cells in the pathological progression of rheumatoid arthritis (RA). Therefore, elucidating the underlying molecular mechanism of the biologic behaviors in RA-FLSs will be helpful in developing the potent targets for the treatment of RA. We have previously documented that the tumor-like biologic behaviors of RA-FLSs are exacerbated by urokinase-type plasminogen activator receptor (uPAR), a specifically up-regulated receptor in RA-FLSs. Here, we investigate the further mechanism of uPAR and clarify its function in RA-FLSs. We demonstrate that miR-221-3p positively correlates to uPAR and regulates uPAR level in RA-FLSs. Simultaneously, one long noncoding RNA, nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) is identified, which can predictively target miR-221-3p at three sites, indicating a strong possibility of being a competing endogenous RNA in RA-FLSs. Interestingly, NEAT1_1 and miR-221-3p can colocate in the nucleus and cytoplasm in RA-FLSs. Importantly, NEAT1_1 can act as a rheostat for the miR-221-3p/uPAR axis and the downstream JAK signaling. In line with the biologic function, NEAT1_1 negatively regulates the tumor-like characters, and cytokine secretions of RA-FLSs. Collectively, our data provide new insight into the mechanisms of NEAT1_1 in modulating RA-FLSs tumor-like behaviors. The targeting of NEAT1_1 and miR-221-3p/uPAR axis may have a promising therapeutic role in patients with RA.