uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis
uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis
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DOI：
10.1038/cmi.2016.60
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发表时间：
2018-02-01
影响因子：
24.1
通讯作者：
Zheng, Song Guo
中科院分区：
文献类型：
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作者：
Liu, Yan;Pan, Yun Feng;Zheng, Song Guo
尿激酶型纤溶酶原激活剂受体(UPAR)是细胞表面的一种多功能受体，广泛存在于内皮细胞、成纤维细胞和多种恶性肿瘤细胞中。目前的研究表明，在类风湿关节炎(RA)患者的滑膜组织或滑液或血浆中，uPAR过表达。然而，关于uPAR在类风湿关节炎成纤维细胞样滑膜细胞中的作用及其机制的研究有限。我们的研究表明，类风湿关节炎患者成纤维细胞样滑膜细胞中uPAR蛋白的表达显著高于骨关节炎或创伤患者。UPAR基因沉默可显著抑制RA-FLSS细胞的增殖，抑制细胞从G0/G1期向S期的转化，加重细胞凋亡，干扰RA-FLSS细胞的迁移和侵袭，减少PI3K/Akt信号通路的激活，这可能与β1-整合素有关。UPAR基因沉默的RA-FLSS的细胞上清液显著抑制人内皮细胞系HUVECs的迁移和小管形成能力。因此，我们证明uPAR改变了RA-FLSS的生物学特性，并影响RA患者滑膜组织的新生血管生成。这些可能与β1-整合素/PI3K/Akt信号通路有关。这些结果提示，靶向uPAR及其下游信号通路可能对RA有治疗作用。
Urokinase-type plasminogen activator receptor (uPAR), is a multifunctional receptor on cell surface, widely present in endothelial cells, fibroblasts, and a variety of malignant cells. Current studies have suggested that uPAR overexpressed on synovial tissues or in synovial fluid or plasma in patients with rheumatoid arthritis (RA). However, there are limited researches regarding the role of uPAR on fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLSs) and its underlying mechanisms. Here, our studies show that the expression of uPAR protein was significantly higher in fibroblast-like synoviocytes (FLSs) from RA than those from osteoarthritis or traumatic injury patients. uPAR gene silencing significantly inhibited RA-FLSs cell proliferation, restrained cell transformation from the G0/G1 phase to S phase, aggravated cell apoptosis, interfered with RA-FLSs cell migration and invasion, and reduced activation of the PI3K/Akt signaling pathway, which may be associated with beta 1-integrin. Cell supernatants from uPAR gene-silenced RA-FLSs markedly inhibited the migration and tubule formation ability of the HUVECs (a human endothelial cell line). Therefore, we demonstrate that uPAR changes the biological characteristics of RA-FLSs, and affects neoangiogenesis of synovial tissues in patients with RA. All of these may be associated with the beta 1-integrin/PI3K/Akt signaling pathway. These results imply that targeting uPAR and its downstream signal pathway may provide therapeutic effects in RA.