microRNAs have been reported to play important roles in the pathogenesis of rheumatoid arthritis (RA). This study examined the effects of miR-522 on the biological behaviors of RA synovial fibroblasts. The expression levels of miR-522 and relevant genes were measured by quantitative real-time PCR. The protein levels of cytokines were determined by ELISA assay. The protein levels of matrix metalloproteinases (MMPs) and suppressor of cytokine signaling 3 (SOCS3) were determined by western blot assay. Luciferase reporter assay was used to confirm the potential target of miR-522. Our results showed that miR-522 was upregulated in synovial fibroblasts from RA patients, and miR-522 expression level was significantly associated with the RA-associated clinical parameters. miR-522 overexpression increased the mRNA and protein expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and MMPs (MMP-1, MMP-3, and MMP-13) in RA synovial fibroblasts. Lipopolysaccharide induced the upregulation of TNF-α, IL-1β, and MMPs in RA synovial fibroblasts, which was reversed by miR-522 knockdown. Bioinformatics analysis identified SOCS3 as a potential target of miR-522, and this target of miR-522 was confirmed by luciferase reporter assay, and miR-522 overexpression suppressed the mRNA and protein expression levels of SOCS3. The enforced expression of SOCS3 attenuated the enhanced effects of miR-522 on mRNA expression levels of TNF-α, IL-1β, and MMPs. Collectively, our results suggested that miR-522 regulated the expression of proinflammatory cytokines and MMPs partly via targeting SOCS3 in RA synovial fibroblasts, which may contribute to pathogenesis of RA.
The tyrosine and phosphoinositide kinases play crucial roles in the regulation of many cancer cell processes including cell survival and cell motility. Anaplastic thyroid carcinoma (ATC) is a rare and deadly type of thyroid cancer, and so far, there are no effective therapeutic compounds for ATC. Herein, we investigate the anticancer activities of PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, in ATC therapy. We found that PP121 is effective at suppressing cell viability, inducing cell apoptosis, and inhibiting cell migration and invasion. The potential anticancer mechanism for PP121 might be its inhibitory effects on phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in ATC cells. Furthermore, PP121 is effective at suppressing ATC tumor growth in vivo. In summary, our studies suggest that PP121 might be a promising therapeutic compound for ATC treatment, which might shed new light on ATC therapy.
The phosphatidylinositol-3-kinase/Akt pathway and receptor tyrosine kinases regulate many tumorigenesis related cellular processes including cell metabolism, cell survival, cell motility, and angiogenesis. Anaplastic thyroid carcinoma (ATC) is a rare type of thyroid cancer with no effective systemic therapy. It has been shown that Akt activation is associated with tumor progression in ATC. Here we observed the additive effect between an Akt inhibitor (MK-2206) and a novel platelet-derived growth factor receptor inhibitor (tyrphostin AG 1296) in ATC therapy. We found an additive effect between MK-2206 and tyrphostin AG 1296 in suppressing ATC cell viability. The combination of MK-2206 and tyrphostin AG 1296 induces additive apoptosis, additive suppression of the Akt signaling pathway, as well as additive inhibition of cell migration and invasion of ATC cells. Furthermore, the combination of MK-2206 and tyrphostin AG 1296 induced additive suppression of ATC tumor growth in vivo. In summary, our studies suggest that the combination of Akt and receptor tyrosine kinase inhibitors may be an efficient therapeutic strategy for ATC treatment, which might shed new light on ATC therapy.
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