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MiR-92a inhibits fibroblast-like synoviocyte proliferation and migration in rheumatoid arthritis by targeting AKT2

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Abstract

Growing data have indicated that the miR-17–92 cluster is implicated in inflammatory response and rheumatoid arthritis (RA). This study was aimed to investigate the effects of miR-92a on the proliferation and migration of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). Our results showed that miR-92a was significantly down-regulated in RA synovial tissue and RA-FLSs, whereas the protein level of AKT2 is increased. Restoration of miR-92a suppressed the proliferation and migration of RA-FLSs. Down-regulation of miR-92a promotes proliferation and migration of normal human FLSs. Dual luciferase reporter gene assay showed that miR-92a could specifically bind with the 3′UTR of AKT2 and significantly repressed the luciferase activity. Down-regulation or up-regulation of miR-92a significantly increased or decreased the protein and phosphorylation levels of AKT2. siRNA-mediated down-regulation of AKT2 significantly prevented cell proliferation and migration of RA-FLSs, which were similar to the effects induced by overexpression of miR-92a. Moreover, AKT2 overexpression rescued miR-92a-mediated suppressive effect on proliferation and migration of RA-FLS. Thus, miR-92a could inhibit the proliferation and migration of RA-FLSs through regulation of AKT2 expression.

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References

  • Akhtar N, Singh AK and Ahmed S 2016 MicroRNA-17 Suppresses TNF-alpha signaling by interfering with TRAF2 and cIAP2 association in rheumatoid arthritis synovial fibroblasts. J. Immunol. 197 2219–2228

    Article  CAS  Google Scholar 

  • Arnett FC, Edworthy SM, Bloch DA, et al. 1988 The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31 315–324

    Article  CAS  Google Scholar 

  • Audo R, Hegglin A, Severac D, Dantec C, Combe B, Hahne M and Morel J 2015 Identification of genes regulating TRAIL-induced apoptosis in rheumatoid arthritis fibroblasts-like synoviocytes. Genes Immun. 16 462–469

    Article  CAS  Google Scholar 

  • Bartok B and Firestein GS 2010 Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunological Rev. 233 233–255

    Article  CAS  Google Scholar 

  • Bottini N and Firestein GS 2013 Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. 9 24–33

    Article  CAS  Google Scholar 

  • Cohen MM Jr. 2013 The AKT genes and their roles in various disorders. Am. J. Med. Genet. Part A. 161A 2931–2937

    Article  Google Scholar 

  • Covic T, Cumming SR, Pallant JF, Manolios N, Emery P, Conaghan PG and Tennant A 2012 Depression and anxiety in patients with rheumatoid arthritis: prevalence rates based on a comparison of the Depression, Anxiety and Stress Scale (DASS) and the hospital, Anxiety and Depression Scale (HADS). BMC Psychiatry 12 6

    Article  Google Scholar 

  • Filkova M, Jungel A, Gay RE and Gay S 2012 MicroRNAs in rheumatoid arthritis: potential role in diagnosis and therapy. BioDrugs Clin. Immunother. Biopharm. Gene Therapy 26 131–141

    CAS  Google Scholar 

  • Guo H, Ingolia NT, Weissman JS and Bartel DP 2010 Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature 466 835–840

    Article  CAS  Google Scholar 

  • Hajiabbasi A, Shenavar Masooleh I, Alizadeh Y, Banikarimi AS and Ghavidel Parsa P 2016 Secondary Sjogren’s syndrome in 83 patients with rheumatoid arthritis. Acta Medica Iranica. 54 448–453

    PubMed  Google Scholar 

  • Hartkamp LM, van Es IE, Malvar Fernandez B, Tak PP, Reedquist KA 2014 The AGC kinases protein kinase B (PKB) and serum and glucocorticoid kinase (SGK) differentially regulate the metabolic activity and inflammatory activation of rheumatoid arthritis fibroblast-like synoviocytes and human macrophages. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2014-eular.5096

    Article  PubMed  Google Scholar 

  • Kaneko S, Kondo Y, Yokosawa M and Sumida T 2016 Rheumatoid arthritis and cytokines. Nihon Rinsho. 74 913–918

    PubMed  Google Scholar 

  • Kaneshiro S, Ebina K, Shi K, et al. 2014 IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. J. Bone Mineral Metab. 32 378–392

    Article  CAS  Google Scholar 

  • Karouzakis E, Gay RE, Gay S and Neidhart M 2009 Epigenetic control in rheumatoid arthritis synovial fibroblasts. Nat. Rev. Rheumatol. 5 266–272

    Article  CAS  Google Scholar 

  • Kim TH, Choi SJ, Lee YH, Song GG, Ji JD 2012 Combined therapeutic application of mTOR inhibitor and vitamin D(3) for inflammatory bone destruction of rheumatoid arthritis. Med Hypotheses 79 757–760

    Article  CAS  Google Scholar 

  • Lao M, Shi M, Zou Y, et al. 2016 Protein inhibitor of activated STAT3 regulates migration, invasion, and activation of fibroblast-like synoviocytes in rheumatoid arthritis. J. Immunol. 196 596–606

    Article  CAS  Google Scholar 

  • Lefevre S, Knedla A, Tennie C, et al. 2009 Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15 1414–1420

    Article  CAS  Google Scholar 

  • Li GF, Qin YH and Du PQ 2015 Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1alpha signaling. Life Sci. 136 67–72

    Article  CAS  Google Scholar 

  • Li X, Zhang Z, Peng A, et al. 2014 Effect of CD95 on inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. Cell. Immunol. 290 209–216

    Article  CAS  Google Scholar 

  • McInnes IB and Schett G 2011 The pathogenesis of rheumatoid arthritis. New Engl. J Med. 365 2205–2219

    Article  CAS  Google Scholar 

  • Mor A, Abramson SB and Pillinger MH 2005 The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin. Immunol. 115 118–128

    Article  CAS  Google Scholar 

  • Mu N, Gu J, Huang T, et al. 2016 A novel NF-kappaB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis. Sci. Rep. 6 20059

    Article  CAS  Google Scholar 

  • O’Connell RM, Rao DS, Chaudhuri AA and Baltimore D 2010 Physiological and pathological roles for microRNAs in the immune system. Nat. Rev. Immunol. 10 111–122

    Article  Google Scholar 

  • Philippe L, Alsaleh G, Bahram S, Pfeffer S and Georgel P 2013 The miR-17 approximately 92 cluster: A key player in the control of inflammation during rheumatoid arthritis. Front Immunol. 4 70

    Article  Google Scholar 

  • Philippe L, Alsaleh G, Suffert G, et al. 2012 TLR2 expression is regulated by microRNA miR-19 in rheumatoid fibroblast-like synoviocytes. J. Immunol. 188 454–461

    Article  CAS  Google Scholar 

  • Rensing KL, de Jager SC, Stroes ES, et al. 2014 Akt2/LDLr double knockout mice display impaired glucose tolerance and develop more complex atherosclerotic plaques than LDLr knockout mice. Cardiovasc. Res. 101 277–287

    Article  CAS  Google Scholar 

  • Sakai A, Saitow F, Maruyama M, et al. 2017 MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain. Nat. Commun. 8 16079

    Article  Google Scholar 

  • Shen YH, Zhang L, Ren P, et al. 2013 AKT2 confers protection against aortic aneurysms and dissections. Circulation Res. 112 618–632

    Article  CAS  Google Scholar 

  • Trenkmann M, Brock M, Gay RE, Michel BA, Gay S and Huber LC 2013 Tumor necrosis factor alpha-induced microRNA-18a activates rheumatoid arthritis synovial fibroblasts through a feedback loop in NF-kappaB signaling. Arthritis Rheum. 65 916–927

    Article  CAS  Google Scholar 

  • Wang SH, Wu XC, Zhang MD, Weng MZ, Zhou D and Quan ZW 2016 Long noncoding RNA H19 contributes to gallbladder cancer cell proliferation by modulated miR-194-5p targeting AKT2. Tumour Biol. 37 9721–9730

    Article  CAS  Google Scholar 

  • Xing R, Jin Y, Sun L, et al. 2016 Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis. Clin. Exp. Immunol. 184 147–158

    Article  CAS  Google Scholar 

  • Xu X, Chen H, Zhang Q, Xu J, Shi Q and Wang M 2017 MiR-650 inhibits proliferation, migration and invasion of rheumatoid arthritis synovial fibroblasts by targeting AKT2. Biomed. Pharmacother. 88 535–541

    Article  CAS  Google Scholar 

  • Yang S and Yang Y 2015 Downregulation of microRNA221 decreases migration and invasion in fibroblastlike synoviocytes in rheumatoid arthritis. Mol. Med. Rep. 12 2395–2401

    Article  CAS  Google Scholar 

  • Yu H, Littlewood T and Bennett M 2015 Akt isoforms in vascular disease. Vasc. Pharmacol. 71 57–64

    Article  CAS  Google Scholar 

  • Yuan Y, Shen Y, Xue L and Fan H 2013 miR-140 suppresses tumor growth and metastasis of non-small cell lung cancer by targeting insulin-like growth factor 1 receptor. PLoS One 8 e73604

    Article  CAS  Google Scholar 

  • Zhang M, Liu Q, Mi S, et al. 2011 Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression. J. Immunol. 186 4716–4724

    Article  CAS  Google Scholar 

  • Zheng F, Liao YJ, Cai MY, et al. 2012 The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut 61 278–289

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by National Science Foundation of China (No. 30801159), the 12th Five Year Programs for the Medical Research of Chinese PLA (CWS12J014), The Capital Health Research and Development of Special grant (39770714 and 2016-3-5071).

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Authors and Affiliations

  1. Department of Orthopaedics, 309th Hospital of Chinese PLA, Beijing, 100091, People’s Republic of China

    Fang-Yuan Yu, Cong-Qin Xie, Chang-liang Jiang, Ji-Tong Sun, Hui-Cheng Feng, Chao Li & Xun-Wu Huang

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  1. Fang-Yuan Yu
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  2. Cong-Qin Xie
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  3. Chang-liang Jiang
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  4. Ji-Tong Sun
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  5. Hui-Cheng Feng
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  7. Xun-Wu Huang
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Correspondence to Xun-Wu Huang.

Additional information

Communicated by Ullas Kolthur-Seetharam.

Corresponding editor: Ullas Kolthur-Seetharam

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Yu, FY., Xie, CQ., Jiang, Cl. et al. MiR-92a inhibits fibroblast-like synoviocyte proliferation and migration in rheumatoid arthritis by targeting AKT2. J Biosci 43, 911–919 (2018). https://doi.org/10.1007/s12038-018-9803-0

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  • DOI: https://doi.org/10.1007/s12038-018-9803-0

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