Knockdown of sphingosine kinase 1 inhibits the migration and invasion of human rheumatoid arthritis fibroblast-like synoviocytes by down-regulating the PI3K/AKT activation and MMP-2/9 production in vitro

Abstract

To investigate the potential regulation of sphingosine kinase 1 (SPHK1) on the migration, invasion, and matrix metalloproteinase (MMP) expression in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were transfected control siRNA or SPHK1 siRNA. The migration and invasion of unmanipulated control, control siRNA or SPHK1 siRNA- transfected RA-FLS in vitro were measured by the transwell system. The relative levels of SPHK1, PI3K, and AKT as well as AKT phosphorylation in RA-FLS were determined by Western blot. The levels of MMP-2/9 secreted by RA-FLS were detected by ELISA. Knockdown of SPHK1 significantly inhibited the spontaneous migration and invasion of RA-FLS, accompanied by significantly reduced levels of PI3K expression and AKT phosphorylation. Similarly, treatment with LY294002, an inhibitor of the PI3K/AKT pathway, inhibited the migration and invasion of RA-FLS. Knockdown of SPHK1 and treatment with the inhibitor synergistically inhibited the migration and invasion of RA-FLS, by further reducing the levels of PI3K expression and AKT phosphorylation. In addition, knockdown of SPHK1 or treatment with LY294002 inhibited the secretion of MMP-2 and MMP-9, and both synergistically reduced the production of MMP-2 and MMP-9 in RA-FLS in vitro. Knockdown of SPHK1 expression inhibits the PI3K/AKT activation, MMP-2 and MMP-9 expression, and human RA-FLS migration and invasion in vitro. Potentially, SPHK1 may be a novel therapeutic target for RA.

miR-218 inhibits the invasion and migration of colon cancer cells by targeting the PI3K/Akt/mTOR signaling pathway

“…The activation of the PI3K signaling pathway is also associated with the hyper-expression of MMP, which accelerates tumor migration and invasion (48)(49)(50)(51). Our results revealed that the activation of the PI3K/Akt/mTOR signaling pathway was enhanced and the expression levels of MMP9 were significantly higher in thecolon cancer tissues compared with the non-tumor tissues.…”

Rictor regulates the vasculogenic mimicry of melanoma via the AKT‐MMP‐2/9 pathway

“…In addition, MMP‐2 and MMP‐9 serve as important downstream effectors of AKT 10, 23, 24 and are involved in cell motility and VM formation 10, 26. Therefore, the hypothesis that Rictor regulates VM via the AKT‐MMP‐2/9 pathway is reasonable.…”

“…A recent study verified that mTORC1 is involved in the VM of glioma via hypoxia-inducible factor-1 alpha [6], indicating that mTORC2 may also play a role in VM. Moreover, the mTORC2 complex can phosphorylate and activate AKT at Ser 473 [20,21], which is the central component in the PI3K-AKT pathway [22], and regulate the expression of downstream matrix metalloproteinases (MMPs) [23][24][25]. MMPs have also been confirmed to be involved in angiogenesis [26] and VM [10].…”

Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis

“…We found that IL‐21 activates the PI3K/AKT, STAT‐3 and ERK1/2 pathways in RA‐FLS, and that activation of AKT, STAT‐3, ERK1/2 and MEK1/2 was detectable 5 min after stimulation, suggesting that stimulation is triggered directly by IL‐21. The ERK pathway was reported to participate in the inflammatory response of RA‐FLS, and the PI3K/AKT and STAT‐3 pathways are crucial for the invasion of RA‐FLS cells . We found that blocking these pathways with specific kinase inhibitors inhibited IL‐21‐induced RA‐FLS migration significantly, and decreased MMP‐3 and MMP‐9 secretion.…”

“…[Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] participate in the inflammatory response of RA-FLS, and the PI3K/AKT and STAT-3 pathways are crucial for the invasion of RA-FLS cells [37]. We found that blocking these pathways with specific kinase inhibitors inhibited IL-21induced RA-FLS migration significantly, and decreased MMP-3 and MMP-9 secretion.…”