Smoothened Regulates Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Activation of Rho GTPase Signaling.
Smoothened Regulates Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Activation of Rho GTPase Signaling.
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Smoothened 通过激活 Rho GTPase 信号传导调节类风湿关节炎中成纤维细胞样滑膜细胞的迁移
DOI：
10.3389/fimmu.2017.00159
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发表时间：
2017
影响因子：
7.3
通讯作者：
Zheng SG
中科院分区：
文献类型：
--
作者：
Peng WX;Zhu SL;Zhang BY;Shi YM;Feng XX;Liu F;Huang JL;Zheng SG
成纤维细胞样滑膜细胞(FLSS)在类风湿关节炎(RA)中获得侵袭性表型，其特征是迁移能力增强和固有的侵袭性。Smos是Sonic Hedgehog(Shh)信号的关键成分，参与肿瘤细胞的侵袭和转移。本研究的目的是研究Smo在细胞迁移调控中的作用，并探讨其潜在的分子机制(S)。从RA滑膜中分离出FLSS。Smo激动剂(紫杉胺)、Smo拮抗剂(KAAD-环胺)或针对Smo基因的小干扰RNA(Smo-siRNA)可调节RA-Fls的ShH水平。实时荧光定量聚合酶链式反应和免疫印迹分析检测Smo的表达。Transwell法检测细胞迁移，下拉法检测Rho GTP酶活性。与对照组相比，与紫杉醇孵育后，细胞迁移和Rho GTP酶信号的激活显著增加(P <； 0.05)。然而，KAAD-环胺处理或Smo-siRNA转染可抑制RA-Fls的迁移，并显示Rho GTPase信号的抑制作用。综上所述，这些结果提示Smo通过激活Rho GTPase信号在RA-FLSS的迁移中发挥重要作用，并可能参与RA的进展，因此靶向Shh信号在RA患者中可能具有治疗潜力。
Fibroblast-like synoviocytes (FLSs) acquire aggressive phenotypes characterized with enhanced migration abilities and inherent invasive qualities in rheumatoid arthritis (RA). Smoothened (Smo) is a key component of sonic hedgehog (Shh) signaling and contributes to tumor cell invasion and metastasis. The objective of this study is to investigate the role of Smo in the modulation of cell migration and explore the underlying molecular mechanism(s). FLSs were isolated from RA synovium. Shh levels were regulated by a Smo agonist (purmorphamine), Smo antagonist (KAAD-cyclopamine), or small interfering RNA targeting the Smo gene (Smo-siRNA) in RA-FLSs. Expression of Smo was detected by real-time PCR and western blot analysis. Cell migration was examined by Transwell assay and activation of Rho GTPases was measured by pull-down assays. Incubation with purmorphamine resulted in a significant increase of cell migration and activation of Rho GTPase signaling compared to controls (P < 0.05). However, treatment with KAAD-cyclopamine or transfection with Smo-siRNA suppressed migration of RA-FLSs and showed an inhibitory effect of Rho GTPase signaling. Together, these results suggest that Smo plays an important role in RA-FLSs migration through activation of Rho GTPase signaling and may contribute to progression of RA, thus, targeting Shh signal may have a therapeutic potential in patients with RA.