LncRNA NEAT1_1 suppresses tumor-like biologic behaviors of fibroblast-like synoviocytes by targeting the miR-221-3p/uPAR axis in rheumatoid arthritis

Abstract

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.

RA Fibroblast-Like Synoviocytes Derived Extracellular Vesicles Promote Angiogenesis by miRNA-1972 Targeting p53/mTOR Signaling in Vascular Endotheliocyte

“…RA FLSs is a crucial determinant of RA pathogenesis that undergo abnormal activation by pro-inflammatory cytokines, interact with neutrophils to accelerate pathogenic adaptive immunity, and contribute to joint damage (40)(41)(42). Accumulating evidence showed activated RA FLSs possess lots of biological characteristics, such as hyperproliferation, migration and tissue invasion which are similar to tumor cells (27). The tumor-like biologic characteristics of RA FLSs are further lead to pannus formation, recruiting inflammatory cells infiltrate into local joints and resulting in cartilage destruction and bone erosion.…”

“…miRNAs have been verified involved in regulating RA FLSs functions. miR-221-3p expedites tumor-like behavior of RA FLSs via uPAR pathway ( 27 ). miRNA-146a-5p can suppress pannus formation in CIA mice ( 2 ).…”

“…Proteins were prepared as we previously documented ( 27 ). Total proteins were extracted from cells with RIPA lysis buffer mixed with phenylmethyl-sulfonyl fluoride (PMSF) and phosphatase inhibitor cocktail I (MedChemExpress, China).…”

“…miR-1972 Is Upregulated in LPS Stimulated RA FLSs Derived EVs miRNAs of RA FLSs has been verified to exert a pro-inflammatory role in local joints, modulate the tumor-like behavior of RA FLSs, and result in bone destruction (25)(26)(27). However, whether RA FLSs derived miRNAs can regulate the angiogenesis is unclear.…”

“…miRNA expression in RA FLSs has been identified to lead to the production of proinflammatory cytokines or metalloproteinases, increased proliferation and survival in RA FLSs (25). We have previously reported that RA FLSs derived miR-221-3p facilitate the tumorlike behavior of RA FLSs, down regulation of miR-221-3p can mitigate the tumor-like character (26,27). Simultaneously, miRNA in RA FLSs derived exosomes have the potential to ignite local inflammation and attenuate osteoclastogenesis (25).…”