Knockdown of YAP/TAZ Inhibits the Migration and Invasion of Fibroblast Synovial Cells in Rheumatoid Arthritis by Regulating Autophagy

Zhou, Wei; Shen, Qiang; Wang, Hui; Yang, Jie; Zhang, Chen; Deng, Zijing; Wu, Keyan; Zhou, Yang; Zeng, Jing; Zhang, Yu; Shen, Weishou

doi:10.1155/2020/9510594

Cited by 25 publications

(21 citation statements)

References 42 publications

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“…Similar effects were seen with RANKL, where Peficitinib and Tofacitinib decreased expression in RAFLS ( 34 ). Other potential mechanisms include the YAP pathway which has been implicated in RAFLS invasiveness ( 59 , 60 ). Indeed, studies in fibroblasts from other disease settings have shown complex interactions between metabolic pathways and YAP/TAZ signalling ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Targeting JAK-STAT Signalling Alters PsA Synovial Fibroblast Pro-Inflammatory and Metabolic Function

et al. 2021

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ObjectivesPsoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity.MethodsPrimary PsAFLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of Oncostatin M (OSM). pSTAT3 expression in response to OSM was quantified by Western Blot analysis. Pro-inflammatory cytokines/chemokines were quantified by ELISA and cell migration by wound-repair scratch assays. Invasive capacity was examined using Matrigel™ invasion chambers and MMP multiplex MSD assays. PsAFLS bioenergetics was assessed using the Seahorse XFe Extracellular Flux Analyzer, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and oxidative phosphorylation (OCR). In parallel, inflammatory, invasive, and migratory genes were quantified by RT-PCR.ResultsOSM induces pSTAT3 expression in PsAFLS. OSM-induced secretion of MCP-1 and IL-6 was inhibited by all JAKi with Peficitinib, Baricitinib and Upadacitinib showing the greatest effect. In contrast, JAKi had no significant impact on IL-8 expression in response to OSM. PsAFLS cell invasion, migratory capacity and MMP1, 3, and 9 were suppressed following JAKi treatment, with Peficitinib showing the greatest effect. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsAFLS, where JAKi significantly decreased glycolysis and the ECAR/OCR, resulting in a shift to a more quiescent phenotype, with Peficitinib demonstrating the most pronounced effect.ConclusionThis study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis. This inhibition shows effective suppression of inflammatory mechanisms that drive pathogenic functions of PsAFLS, further supporting the role of JAKi as a therapeutic target for the treatment of PsA.

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Section: Discussionmentioning

confidence: 99%

Targeting JAK-STAT Signalling Alters PsA Synovial Fibroblast Pro-Inflammatory and Metabolic Function

et al. 2021

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“…IL-38 and IL-36 affect synovial cell proliferation, migration, and invasion, and they also modulate synovial cell autophagy. Autophagy is reported to modulate cell migration and invasion through different mechanisms [ 35 – 37 ]. Therefore, the effect of IL-38 and autophagy interaction on synovial cell proliferation, migration, and invasion was further studied.…”

Section: Discussionmentioning

confidence: 99%

IL-38 and IL-36 Target Autophagy for Regulating Synoviocyte Proliferation, Migration, and Invasion in Rheumatoid Arthritis

Hao

Liu

2021

Disease Markers

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Rheumatoid arthritis (RA) is an autoimmune disease leading to severe joint damage and disability. Fibroblast-like synoviocytes (FLSs) mostly contribute to the joint inflammation and destruction in RA through distinct mechanisms. However, little is known about newly discovered interleukin- (IL-) 36 and IL-38 involving in the pathology of RA. Here, we assessed the effect of IL-36 and IL-38 on RA-FLS function using IL-36 and IL-38 overexpression plasmids. We found that IL-36 inhibited synoviocytes proliferation while IL-38 showed an opposite influence. Furthermore, IL-36 and IL-38 significantly sequestered or accelerated RA-FLS migration and invasion capacity, respectively. Mechanically, IL-36 and IL-38 targeted autophagy for RA-FLS modulation. Using autophagy inhibitor 3-MA and inducer compound rapamycin, we found that autophagy negatively regulated the survival, migration, and invasion of synovial cells. Based on these results, IL-38 in combination with autophagy inhibitor 3-MA treatment demonstrated the strongest blockage of the above three activities of RA-FLS, and IL-38 overexpression reversed rapamycin-inhibited cell proliferation, migration, and invasion. Moreover, injection of IL-36 can improve the symptoms of RA in a rat model of RA. Taken together, we conclude that IL-38 and IL-36 target autophagy for regulating synoviocyte proliferation, migration, and invasion in RA.

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“…Human HCC cell lines SMMC-7721 and SK-HEP1, purchased from Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences (Shanghai, China), were routinely ma mod one), supplemented with 10% fetal bovine serum (FBS, Gibco, Carlsbad, CA, USA) and 1% penicillin-streptomycin, and incubated in a moist incubator at 37 °C with 5% CO 2 . To silence the expression of YAP, lentiviruses expressing shYAP or shNC was constructed in our lab [11] and used to transduce into SMMC-7721 cells. After selection with 0.5 for 14 days, stable YAP knockdown SMMC-7721 cells were generated and verified by Western blotting.…”

Section: Methodsmentioning

confidence: 99%

Apigenin regulates the migration, invasion, and autophagy of hepatocellular carcinoma cells by downregulating YAP

Jing¹,

Xie²,

Zhang³

et al. 2022

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Apigenin is an edible flavonoid with anticancer properties; however, the underlying mechanisms in hepatocellular carcinoma (HCC) remain to be clarified. In the present study, we demonstrated that apigenin decreased the viability of both SMMC-7721 and SK-Hep1 cells in a dose-dependent manner, and inhibited the migration and invasion of HCC cells with different metastatic potential by regulating actin cytoskeletal rearrangements. Moreover, we showed that apigenin decreased the expression of YAP, and subsequently reduced migration and invasion by modulating the expression of the epithelial-mesenchymal transition (EMT) markers, and promoted the autophagy of HCC cells by regulating the expression of autophagy-related genes. Collectively, the present findings might provide a novel mechanism for the therapeutic application of apigenin in HCC.

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Knockdown of YAP/TAZ Inhibits the Migration and Invasion of Fibroblast Synovial Cells in Rheumatoid Arthritis by Regulating Autophagy

Cited by 25 publications

References 42 publications

Targeting JAK-STAT Signalling Alters PsA Synovial Fibroblast Pro-Inflammatory and Metabolic Function

Targeting JAK-STAT Signalling Alters PsA Synovial Fibroblast Pro-Inflammatory and Metabolic Function

IL-38 and IL-36 Target Autophagy for Regulating Synoviocyte Proliferation, Migration, and Invasion in Rheumatoid Arthritis

Apigenin regulates the migration, invasion, and autophagy of hepatocellular carcinoma cells by downregulating YAP

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