我们前期研究发现，尿激酶型纤溶酶原激活物受体（uPAR）在类风湿关节炎（RA）患者成纤维样滑膜细胞（FLS）中表达增高，能促进FLS增殖、迁移、侵袭，机制上可能与PI3K/AKT通路激活有关，但在RA滑膜中调控uPAR表达的分子机制尚不明确。研究发现miR-221可结合uPAR的3'UTR区而调控uPAR表达，miRNA表达受多重机制调控，LncRNA是其中一种重要调控方式。我们通过生物信息学分析发现数个可能参与miR-221调控的LncRNAs，其中HOTAIR能激活RA-FLS分泌基质金属蛋白酶，造成骨质破坏等。因此我们假设，HOTAIR在RA-FLS中可能通过miR-221调控uPAR表达，参与RA-FLSs异常增殖和侵袭等改变。我们将通过FLS及动物模型，采用CRISPR/Cas9等基因敲低/过表达技术，探讨RA滑膜中HOTAIR调控miR-221而调节uPAR表达的分子机制。

Urokinase-type plasminogen activator receptor (uPAR) is a multifunctional receptor on cell surface.Our previous studies report that elevated expression of uPAR markedly affects the proliferation, migration, and invasiveness of fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLSs) and the PI3K/Akt signaling pathway may be responsible for mediating effects of uPAR on FLSs.However, the molecular mechanisms underlying regulation of uPAR overexpression on RA-FLSs are unclear now.We found that miRNA-221 could regulates uPAR expression in RA-FLSs and some malignant cells. By performing bioinformatics analysis,we identified some LncRNAs as targets that may closely related to the physical interaction with miR-221,especially HOTAIR,which contributes to the RA pathogenesis through activation of matrix metalloproteinases in RA synoviocytes. Therefore, we hypothesize that LncRNA HOTAIR may bind to miR-221 and then to promote uPAR expression in RA-FLSs,which affect the tumor-like biologic behaviors of FLSs.In current study, we will utilize FLSs and animal models to investigate the interaction of LncRNA HOTAIR with miRNA-221 and their roles on modulating uPAR expression by using molecular/cellular approaches.