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LncRNA MEG3 inhibits the inflammatory response of ankylosing spondylitis by targeting miR-146a

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Abstract

Ankylosing spondylitis (AS) is a progressive systemic disease characterized by chronic inflammation response of the sacroiliac joint and spine. Long non-coding RNAs (lncRNAs) are widely involved in the regulation of various diseases. However, the role of lncRNA maternally expressed gene 3 (MEG3) in the inflammatory response of AS has not been studied. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in tissues and cells. The expression levels of MEG3, microRNA-146a (miR-146a), and inflammatory cytokines were measured by quantitative real-time PCR (qRT-PCR). Correlation between MEG3 or miR-146a and inflammatory cytokines was analyzed by Pearson analysis. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to clarify the interaction between MEG3 and miR-146a. MEG3 was downregulated in AS patients, negatively correlated with the levels of IL-1β, IL-6, and TNF-α, and blocked the inflammatory response of AS. MiR-146a was upregulated in AS patients and could interact with MEG3. The expression of miR-146a was positively correlated with IL-1β, IL-6, and TNF-α levels. Overexpression of miR-146a reversed the inhibitory effect of abnormal MEG3 expression on inflammatory cytokines. LncRNA MEG3 plays an anti-inflammatory role in AS partially through targeting miR-146a, which provides a potential new means for the treatment of AS patients.

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References

  1. Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369:1379–1390. https://doi.org/10.1016/S0140-6736(07)60635-7

    Article  PubMed  Google Scholar 

  2. Zochling J, Braun J (2008) Mortality in ankylosing spondylitis. Clin Exp Rheumatol 26:S80–S84

    CAS  PubMed  Google Scholar 

  3. Sieper J, Appel H, Braun J, Rudwaleit M (2008) Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes. Arthritis Rheum 58:649–656. https://doi.org/10.1002/art.23260

    Article  PubMed  Google Scholar 

  4. Raychaudhuri SP, Deodhar A (2014) The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun 48–49:128–133. https://doi.org/10.1016/j.jaut.2014.01.015

    Article  PubMed  Google Scholar 

  5. Sampaio-Barros PD, Bertolo MB, Kraemer MH, Neto JF, Samara AM (2001) Primary ankylosing spondylitis: patterns of disease in a Brazilian population of 147 patients. J Rheumatol 28:560–565

    CAS  PubMed  Google Scholar 

  6. Bakland G, Gran JT, Nossent JC (2011) Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis 70:1921–1925. https://doi.org/10.1136/ard.2011.151191

    Article  PubMed  Google Scholar 

  7. Lalevee S, Feil R (2015) Long noncoding RNAs in human disease: emerging mechanisms and therapeutic strategies. Epigenomics 7:877–879. https://doi.org/10.2217/epi.15.55

    Article  CAS  PubMed  Google Scholar 

  8. Kwok ZH, Tay Y (2017) Long noncoding RNAs: lincs between human health and disease. Biochem Soc Trans 45:805–812. https://doi.org/10.1042/BST20160376

    Article  CAS  PubMed  Google Scholar 

  9. Tay Y, Rinn J, Pandolfi PP (2014) The multilayered complexity of ceRNA crosstalk and competition. Nature 505:344–352. https://doi.org/10.1038/nature12986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Xie Z, Li J, Wang P, Li Y, Wu X, Wang S, Su H, Deng W, Liu Z, Cen S, Ouyang Y, Wu Y, Shen H (2016) Differential expression profiles of long noncoding RNA and mRNA of osteogenically differentiated mesenchymal stem cells in ankylosing spondylitis. J Rheumatol 43:1523–1531. https://doi.org/10.3899/jrheum.151181

    Article  CAS  PubMed  Google Scholar 

  11. Li X, Chai W, Zhang G, Ni M, Chen J, Dong J, Zhou Y, Hao L, Bai Y, Wang Y (2017) Down-regulation of lncRNA-AK001085 and its influences on the diagnosis of ankylosing spondylitis. Med Sci Monit 23:11–16. https://doi.org/10.12659/msm.898915

    Article  CAS  Google Scholar 

  12. Zhong H, Zhong M (2019) LINC00311 is overexpressed in ankylosing spondylitis and predict treatment outcomes and recurrence. BMC Musculoskelet Disord 20:278. https://doi.org/10.1186/s12891-019-2647-4

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lan X, Ma H, Zhang Z, Ye D, Min J, Cai F, Luo J (2018) Downregulation of lncRNA TUG1 is involved in ankylosing spondylitis and is related to disease activity and course of treatment. Biosci Trends 12:389–394. https://doi.org/10.5582/bst.2018.01117

    Article  CAS  PubMed  Google Scholar 

  14. Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, Cheunsuchon P, Louis DN, Klibanski A (2010) Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res 70:2350–2358. https://doi.org/10.1158/0008-5472.CAN-09-3885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Balik V, Srovnal J, Sulla I, Kalita O, Foltanova T, Vaverka M, Hrabalek L, Hajduch M (2013) MEG3: a novel long noncoding potentially tumour-suppressing RNA in meningiomas. J Neurooncol 112:1–8. https://doi.org/10.1007/s11060-012-1038-6

    Article  CAS  PubMed  Google Scholar 

  16. Ghafouri-Fard S, Taheri M (2019) Maternally expressed gene 3 (MEG3): A tumor suppressor long non coding RNA. Biomed Pharmacother 118:109129. https://doi.org/10.1016/j.biopha.2019.109129

    Article  CAS  PubMed  Google Scholar 

  17. Wang D, Fu CW, Fan DQ (2019) Participation of tumor suppressors long non-coding RNA MEG3, microRNA-377 and PTEN in glioma cell invasion and migration. Pathol Res Pract. https://doi.org/10.1016/j.prp.2019.152558

    Article  PubMed  Google Scholar 

  18. Wang M, Li C, Zhang Y, Zhou X, Liu Y, Lu C (2019) LncRNA MEG3-derived miR-361-5p regulate vascular smooth muscle cells proliferation and apoptosis by targeting ABCA1. Am J Transl Res 11:3600–3609

    PubMed  PubMed Central  Google Scholar 

  19. Zhang X, Wu N, Wang J, Li Z (2019) LncRNA MEG3 inhibits cell proliferation and induces apoptosis in laryngeal cancer via miR-23a/APAF-1 axis. J Cell Mol Med. https://doi.org/10.1111/jcmm.14549

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liu W, Huang L, Zhang C, Liu Z (2019) lncRNA MEG3 is downregulated in ankylosing spondylitis and associated with disease activity, hospitalization time and disease duration. Exp Ther Med 17:291–297. https://doi.org/10.3892/etm.2018.6921

    Article  CAS  PubMed  Google Scholar 

  21. Smolen JS, Braun J, Dougados M, Emery P, Fitzgerald O, Helliwell P, Kavanaugh A, Kvien TK, Landewe R, Luger T, Mease P, Olivieri I, Reveille J, Ritchlin C, Rudwaleit M, Schoels M, Sieper J, Wit M, Baraliakos X, Betteridge N, Burgos-Vargas R, Collantes-Estevez E, Deodhar A, Elewaut D, Gossec L, Jongkees M, Maccarone M, Redlich K, van den Bosch F, Wei JC, Winthrop K, van der Heijde D (2014) Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis 73:6–16. https://doi.org/10.1136/annrheumdis-2013-203419

    Article  PubMed  Google Scholar 

  22. Dougados M, Baeten D (2011) Spondyloarthritis. Lancet 377:2127–2137. https://doi.org/10.1016/S0140-6736(11)60071-8

    Article  PubMed  Google Scholar 

  23. Maxwell LJ, Zochling J, Boonen A, Singh JA, Veras MM, Tanjong Ghogomu E, Benkhalti Jandu M, Tugwell P, Wells GA (2015) TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst Rev 4:CD005468. https://doi.org/10.1002/14651858.CD005468.pub2

    Article  Google Scholar 

  24. Molnar C, Scherer A, Baraliakos X, de Hooge M, Micheroli R, Exer P, Kissling RO, Tamborrini G, Wildi LM, Nissen MJ, Zufferey P, Bernhard J, Weber U, Landewe RBM, van der Heijde D, Ciurea A, Rheumatologists of the Swiss Clinical Quality Management P (2018) TNF blockers inhibit spinal radiographic progression in ankylosing spondylitis by reducing disease activity: results from the Swiss Clinical Quality Management cohort. Ann Rheum Dis 77:63–69. https://doi.org/10.1136/annrheumdis-2017-211544

    Article  CAS  Google Scholar 

  25. Baeten D, Sieper J, Braun J, Baraliakos X, Dougados M, Emery P, Deodhar A, Porter B, Martin R, Andersson M, Mpofu S, Richards HB, Group MS, Group MS (2015) Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N Engl J Med 373:2534–2548. https://doi.org/10.1056/NEJMoa1505066

    Article  CAS  Google Scholar 

  26. Xu Z, Zhou X, Li H, Chen Q, Chen G (2019) Identification of the key genes and long noncoding RNAs in ankylosing spondylitis using RNA sequencing. Int J Mol Med 43:1179–1192. https://doi.org/10.3892/ijmm.2018.4038

    Article  CAS  PubMed  Google Scholar 

  27. Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci USA 103:12481–12486. https://doi.org/10.1073/pnas.0605298103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bitar A, Aung KM, Wai SN, Hammarstrom ML (2019) Vibrio cholerae derived outer membrane vesicles modulate the inflammatory response of human intestinal epithelial cells by inducing microRNA-146a. Sci Rep 9:7212. https://doi.org/10.1038/s41598-019-43691-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu HY, Wang ZY, Chen JF, Wang TY, Wang LL, Tang LL, Lin XY, Zhang CW, Chen BC (2015) Association between ankylosing spondylitis and the miR-146a and miR-499 polymorphisms. PLoS ONE ONE 10:e0122055. https://doi.org/10.1371/journal.pone.0122055

    Article  CAS  Google Scholar 

  30. Qian BP, Ji ML, Qiu Y, Wang B, Yu Y, Shi W, Luo YF (2016) Identification of serum miR-146a and miR-155 as novel noninvasive complementary biomarkers for ankylosing spondylitis. Spine (Phila Pa 1976) 41:735–742. https://doi.org/10.1097/BRS.0000000000001339

    Article  Google Scholar 

  31. Di G, Kong L, Zhao Q, Ding T (2018) MicroRNA-146a knockdown suppresses the progression of ankylosing spondylitis by targeting dickkopf 1. Biomed Pharmacother 97:1243–1249. https://doi.org/10.1016/j.biopha.2017.11.067

    Article  CAS  PubMed  Google Scholar 

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Li, Y., Zhang, S., Zhang, C. et al. LncRNA MEG3 inhibits the inflammatory response of ankylosing spondylitis by targeting miR-146a. Mol Cell Biochem 466, 17–24 (2020). https://doi.org/10.1007/s11010-019-03681-x

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