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Long non-coding RNA GAS5 suppresses rheumatoid arthritis progression via miR-128-3p/HDAC4 axis

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Abstract

Rheumatoid arthritis (RA) is a highly relevant public health problem. RA fibroblast-like synoviocytes (RAFLSs) play an important role in RA progression. Long non-coding RNA growth arrest-specific transcript 5 (GAS5) could improve RA by inducing RAFLSs apoptosis. However, the mechanism of GAS5 in RA remains unclear. RT-qPCR detected the expressions of GAS5, microRNA-128-3p (miR-128-3p), and histone deacetylase 4 (HDAC4) in RA synovial tissues and RAFLSs. Proliferation, apoptosis, migration, and invasion were measured by Cell Counting Kit-8 assay (CCK-8), flow cytometry, and transwell assays, severally. The protein levels of B-cell lymphoma-2 (Bcl-2), C-caspase 3, Bcl-2 related X protein (Bax), Tumor Necrosis factor-α (TNF-α), Interleukin 6 (IL-6), Interleukin 17 (IL-17), HDAC4, phosphorylation-protein kinase B (p-AKT), AKT, a phosphorylation-mechanistic target of rapamycin (p-mTOR), and mTOR were assessed by western blot assay. The interaction between miR-128-3p and GAS5 or HDAC4 was predicted by ENCORI or TargetScan Human and verified by the dual-luciferase reporter, RNA Immunoprecipitation (RIP), and RNA pull-down assays. GAS5 and HDAC4 were downregulated, and miR-128-3p was upregulated in RA synovial tissues and RAFLSs. Function analysis indicated that GAS5 curbed proliferation, migration, invasion, inflammation, and facilitated apoptosis of RAFLSs. Rescue assay confirmed that miR-128-3p overexpression or HDAC4 knockdown weakened the inhibitory effect of GAS5 or anti-miR-128-3p on RA development. GAS5 acted as a miR-128-3p sponge to upregulate HDAC4 expression. Besides, GAS5/miR-128-3p/HDAC4 axis regulated RA progression partially through the AKT/mTOR pathway. Our studies disclosed that GAS5 restrained inflammation in synovial tissue partly through regulating HDAC4 via miR-128-3p, suggesting a potential lncRNA-targeted therapy for RA treatment.

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Authors and Affiliations

  1. Department of Orthopaedics, Shandong Otolaryngology Hospital, Jinan, Shandong, China

    Tao Peng

  2. Department of Anorectal, Jinan Central Hospital, Shandong Province, Jinan, Shandong, China

    Dehui Ji

  3. Department of Joint Surgery/Sports Medicine, The Second Hospital of Shandong University, Tianqiao District, Unit 1, Building 16, Xinyuan Mingjia, Binhe South Road, Jinan, 250031, Shandong, China

    Yankai Jiang

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  1. Tao Peng
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  2. Dehui Ji
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  3. Yankai Jiang
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TP developed the idea, HJ and YJ collected the clinical samples, TP performed all the complicated laboratory research work at the bench.

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Correspondence to Yankai Jiang.

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Peng, T., Ji, D. & Jiang, Y. Long non-coding RNA GAS5 suppresses rheumatoid arthritis progression via miR-128-3p/HDAC4 axis. Mol Cell Biochem 476, 2491–2501 (2021). https://doi.org/10.1007/s11010-021-04098-1

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  • DOI: https://doi.org/10.1007/s11010-021-04098-1

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