Downregulated MEG3 participates in rheumatoid arthritis via promoting proliferation of fibroblast‑like synoviocytes

Lu,Xin; Qian,Jun

doi:10.3892/etm.2018.7100

Downregulated MEG3 participates in rheumatoid arthritis via promoting proliferation of fibroblast‑like synoviocytes

Authors:
- Xin Lu
- Jun Qian
View Affiliations

Affiliations: Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
Published online on: December 14, 2018 https://doi.org/10.3892/etm.2018.7100
Pages: 1637-1642
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Maternally expressed gene 3 (MEG3) in rheumatoid arthritis (RA) and its underlying mechanism were explored. Synovial tissues from 10 RA patients and 10 controls were collected to detect MEG3 expression in fibroblast‑like synoviocytes (FLS). The relationship between MEG3 expression and TNF‑α was analyzed. After MEG3 knockdown by lentivirus transfection, cell cycle, proliferation, apoptosis, invasion and secretion of inflammatory factors were detected. Furthermore, the effect of MEG3 on STAT3 and PI3K/AKT pathways was explored. MEG3 was downregulated in RA patients, and exogenous TNF‑α treatment could decrease MEG3 expression. After transfection with lentivirus, downregulated MEG3 led to FLS proliferation and secretion of inflammatory cytokines, IL‑6 and IL‑8, improved the invasive ability and inhibited apoptosis. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) results revealed that downregulated MEG3 increased the expression levels of MMP2 and MMP9. Western blotting results showed that downregulated MEG3 activated STAT3 and PI3K/AKT pathways. Downregulated MEG3 was able to promote proliferation and invasion, and inhibit apoptosis of FLS via STAT3 pathway.

View Figures

View References

1	Di Spigna G, Del Puente A, Covelli B, Abete E, Varriale E, Salzano S and Postiglione L: Vitamin D receptor polymorphisms as tool for early screening of severe bone loss in women patients with rheumatoid arthritis. Eur Rev Med Pharmacol Sci. 20:4664–4669. 2016.PubMed/NCBI
2	Calabrò A, Caterino AL, Elefante E, Valentini V, Vitale A, Talarico R, Cantarini L and Frediani B: One year in review 2016: Novelties in the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 34:357–372. 2016.PubMed/NCBI
3	Bellucci E, Terenzi R, La Paglia GM, Gentileschi S, Tripoli A, Tani C and Alunno A: One year in review 2016: Pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 34:793–801. 2016.PubMed/NCBI
4	Flurey CA, Hewlett S, Rodham K, White A, Noddings R and Kirwan J: Men, rheumatoid arthritis, psychosocial impact and self-management: A narrative review. J Health Psychol. 21:2168–2182. 2016. View Article : Google Scholar : PubMed/NCBI
5	Wang C, Wang L, Ding Y, Lu X, Zhang G, Yang J, Zheng H, Wang H, Jiang Y and Xu L: LncRNA structural characteristics in epigenetic regulation. Int J Mol Sci. 18:26592017. View Article : Google Scholar
6	Peng WX, Koirala P and Mo YY: LncRNA-mediated regulation of cell signaling in cancer. Oncogene. 36:5661–5667. 2017. View Article : Google Scholar : PubMed/NCBI
7	Frank S, Aguirre A, Hescheler J and Kurian L: A lncRNA perspective into (re)building the heart. Front Cell Dev Biol. 4:1282016. View Article : Google Scholar : PubMed/NCBI
8	Zhou Y, Zhang X and Klibanski A: MEG3 noncoding RNA: A tumor suppressor. J Mol Endocrinol. 48:R45–R53. 2012. View Article : Google Scholar : PubMed/NCBI
9	Balik V, Srovnal J, Sulla I, Kalita O, Foltanova T, Vaverka M, Hrabalek L and Hajduch M: MEG3: A novel long noncoding potentially tumour-suppressing RNA in meningiomas. J Neurooncol. 112:1–8. 2013. View Article : Google Scholar : PubMed/NCBI
10	Benetatos L, Voulgaris E and Vartholomatos G: DLK1-MEG3 imprinted domain microRNAs in cancer biology. Crit Rev Eukaryot Gene Expr. 22:1–15. 2012. View Article : Google Scholar : PubMed/NCBI
11	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
12	Krause A, Scaletta N, Ji JD and Ivashkiv LB: Rheumatoid arthritis synoviocyte survival is dependent on Stat3. J Immunol. 169:6610–6616. 2002. View Article : Google Scholar : PubMed/NCBI
13	Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM and Holers VM: Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 31:3–18. 2017. View Article : Google Scholar : PubMed/NCBI
14	Fu H, Hu D, Zhang L and Tang P: Role of extracellular vesicles in rheumatoid arthritis. Mol Immunol. 93:125–132. 2018. View Article : Google Scholar : PubMed/NCBI
15	Sehgal PB: Paradigm shifts in the cell biology of STAT signaling. Semin Cell Dev Biol. 19:329–340. 2008. View Article : Google Scholar : PubMed/NCBI
16	Tebbutt NC, Giraud AS, Inglese M, Jenkins B, Waring P, Clay FJ, Malki S, Alderman BM, Grail D, Hollande F, et al: Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med. 8:1089–1097. 2002. View Article : Google Scholar : PubMed/NCBI
17	Ranger JJ, Levy DE, Shahalizadeh S, Hallett M and Muller WJ: Identification of a Stat3-dependent transcription regulatory network involved in metastatic progression. Cancer Res. 69:6823–6830. 2009. View Article : Google Scholar : PubMed/NCBI
18	Matsumoto S, Müller-Ladner U, Gay RE, Nishioka K and Gay S: Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. J Rheumatol. 23:1345–1352. 1996.PubMed/NCBI
19	Yu H and Jove R: The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI
20	Perlman H, Georganas C, Pagliari LJ, Koch AE, Haines K III and Pope RM: Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. J Immunol. 164:5227–5235. 2000. View Article : Google Scholar : PubMed/NCBI
21	Korb A, Pavenstädt H and Pap T: Cell death in rheumatoid arthritis. Apoptosis. 14:447–454. 2009. View Article : Google Scholar : PubMed/NCBI
22	Tolboom TC, van der Helm-Van Mil AH, Nelissen RG, Breedveld FC, Toes RE and Huizinga TW: Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. Arthritis Rheum. 52:1999–2002. 2005. View Article : Google Scholar : PubMed/NCBI
23	Ishiguro N: Cartilage degradation in rheumatoid arthritis. Clin Calcium. 19:347–354. 2009.(In Japanese). PubMed/NCBI
24	Eck SM, Blackburn JS, Schmucker AC, Burrage PS and Brinckerhoff CE: Matrix metalloproteinase and G protein coupled receptors: Co-conspirators in the pathogenesis of autoimmune disease and cancer. J Autoimmun. 33:214–221. 2009. View Article : Google Scholar : PubMed/NCBI
25	Kotake S, Nanke Y, Yago T and Yamanaka H: Serum markers of synovitis and bone metabolism in rheumatoid arthritis. Clin Calcium. 19:362–371. 2009.(In Japanese). PubMed/NCBI
26	Chen Q, Jin M, Yang F, Zhu J, Xiao Q and Zhang L: Matrix metalloproteinases: Inflammatory regulators of cell behaviors in vascular formation and remodeling. Mediators Inflamm. 2013:9283152013. View Article : Google Scholar : PubMed/NCBI