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OP0155 Mdm2-mediated sumoylation of p53 contributes to the migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis
  1. M Shi1,2,
  2. H Xu1,
  3. G Chen2
  1. 1Department of Rheumatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou
  2. 2Department of Rheumatology, The First People's Hospital of Foshan, Foshan, China

Abstract

Background Fibroblast-like synoviocytes (FLSs) in the synovial intimal lining are essential in the maintenance of synovial inflammation and progressive joint destruction in the development of Rheumatoid arthritis (RA). However, the precise molecular mechanisms by which this pathogenic process is regulated are not clearly defined.

Objectives Increasing evidence indicates that p53 plays a critical role in the invasion and metastasis of cancer cells. This study aims to investigate the role of MDM2-mediated sumoylation of p53 in regulating the migration and invasion of fibroblast-like synoviocytes (FLSs) from patients with RA.

Methods Synovial tissues were obtained from OA and RA patients, and then FLSs were separated from synovial tissues. Protein expression was measured by Western bloting or IHC staining. The sumoylation of p53 in cells was determined by immunoprecipitation. A specific inhibitor of MDM2-p53 interaction was used to inhibit the sumoylation of p53. Migration and invasion of FLSs in vitro were measured by the Boyden chamber assay.

Results MDM2, SUMO1, and SUMO2 expression was significantly increased in the synovial tissue and FLSs of RA patients. Stimulation with TNF-α increased MDM2 expression and p53 sumoylation in RA FLSs. MDM2 shRNA inhibited p53 sumoylation, pro-inflammatory cytokines and MMPs expression, and capacity of in vitro migration and invasion in RA FLSs. Inhibition of p53 sumoylation by MDM2 shRNA promoted apotosis and reduced prolifeaation of RA FLSs. p38 MAPK signal pathway was involved in the downstream signal transduction in RA FLSs. Administration of MDM2 shRNA expressiong lentivirus attenuate the severity of rats with collagen-induced arthritis (CIA).

Conclusions Increased MDM2-mediated p53 sumoylation contributes to aberrant aggressive behaviours of RA FLSs. Our findings suggests inhibition of MDM2 or p53 sumoylation might be a a novel therapeutic strategy to prevent synovial invasiveness and joint destruction in RA.

References

  1. Bottini N, Firestein GS. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol. 2013 Jan;9(1):24–33.

  2. Ren Z, Aerts JL, Vandenplas H, et al. Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2. Cell Death Dis. 2016 Dec 22;7(12):e2560.

  3. Lu M, Breyssens H, Salter V, et al. Restoring p53 Function in Human Melanoma Cells by Inhibiting MDM2 and Cyclin B1/CDK1-Phosphorylated Nuclear iASPP. Cancer Cell. 2016 Nov 14;30(5):822–823.

  4. Park JS, Lim MA, Cho ML, et al. p53 controls autoimmune arthritis via STAT-mediated regulation of the Th17 cell/Treg cell balance in mice. Arthritis Rheum. 2013 Apr;65(4):949–59.

References

Acknowledgements This work is supported by grants from the National Natural Science Foundation of China (Grant number 81373182, 81373194, 8150060222 and U1401222). We would like to thank Jinjin Fan for her technical assistance.

Disclosure of Interest None declared

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