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Erschienen in: Clinical and Experimental Medicine 1/2019

21.08.2018 | Original Article

Upregulation of miR-221/222 expression in rheumatoid arthritis (RA) patients: correlation with disease activity

verfasst von: Amira S. Abo ElAtta, Yasser B. M. Ali, Iman H. Bassyouni, Roba M. Talaat

Erschienen in: Clinical and Experimental Medicine | Ausgabe 1/2019

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Abstract

miRNAs are noncoding RNA that play a critical role as fine regulators of gene expression at the posttranscriptional level within cells in numerous autoimmune diseases. miR-221/222 play a role in cancer by regulating cell proliferation, invasion and apoptosis. However, there have been insufficient studies on their role in rheumatoid arthritis (RA). This work is designed to analyze the miR-221/222 expression patterns in peripheral blood mononuclear cells (PBMCs) of patients with RA in comparison with healthy controls using quantitative RT-PCR, in a group of 30 RA patients and 20 healthy controls. The fold change of miR-221/222 expression in PBMCs was significantly elevated (p < 0.01) in RA patients compared with healthy controls. A positive correlation between expression levels of miR-221 and miR-222 was recorded (r = 0.303; p < 0.05). High miR-221/222 expression levels appeared to be elevated with high activity. miR-222 expression in high activity group of RA patients was significantly increased in relation to moderate (p < 0.01) and low (p < 0.001) activity ones with positive correlation (r = 0.363; p < 0.05) between the progress of disease activity and change in miR-222 expression level. ROC analysis showed a sensitivity of 70% and specificity of 75% for miR-221. In miR-222, the sensitivity of 80% and specificity of 70% were recorded. Our data shed some light on the role of miR-221/222 expression in RA patients, and their great potential value as new novel noninvasive biomarkers for disease detection. Therefore; further investigations are warranted to fully elucidate their role in rheumatoid.
Literatur
2.
Zurück zum Zitat Sakr BR, Elfishawi MM, ElArousy MH, et al. Rheumatoid arthritis: a single center Egyptian experience. Immunol Invest. 2018;47(3):293–302.CrossRefPubMed Sakr BR, Elfishawi MM, ElArousy MH, et al. Rheumatoid arthritis: a single center Egyptian experience. Immunol Invest. 2018;47(3):293–302.CrossRefPubMed
3.
Zurück zum Zitat Baillet A, Trocmé C, Berthier S. Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases. Rheumatology. 2010;49(4):671–82.CrossRefPubMed Baillet A, Trocmé C, Berthier S. Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases. Rheumatology. 2010;49(4):671–82.CrossRefPubMed
4.
Zurück zum Zitat Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology. 2006;45:20–5.CrossRefPubMed Zendman AJ, van Venrooij WJ, Pruijn GJ. Use and significance of anti-CCP autoantibodies in rheumatoid arthritis. Rheumatology. 2006;45:20–5.CrossRefPubMed
6.
Zurück zum Zitat Chekulaeva M, Filipowicz W. Mechanisms of miRNA-mediated posttranscriptional regulation in animal cells. Curr Opin Cell Biol. 2009;21:452–60.CrossRefPubMed Chekulaeva M, Filipowicz W. Mechanisms of miRNA-mediated posttranscriptional regulation in animal cells. Curr Opin Cell Biol. 2009;21:452–60.CrossRefPubMed
7.
Zurück zum Zitat Xu WD, Lu MM, Pan HF, et al. Association of microRNA-146a with autoimmune diseases. Inflammation. 2012;35:1525–9.CrossRefPubMed Xu WD, Lu MM, Pan HF, et al. Association of microRNA-146a with autoimmune diseases. Inflammation. 2012;35:1525–9.CrossRefPubMed
8.
Zurück zum Zitat Wang Y, Li Z, He C, et al. MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis. 2010;44:191–7.CrossRefPubMedPubMedCentral Wang Y, Li Z, He C, et al. MicroRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells Mol Dis. 2010;44:191–7.CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Li J, Wan Y, Guo Q, et al. Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther. 2010;12:R81.CrossRefPubMedPubMedCentral Li J, Wan Y, Guo Q, et al. Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis. Arthritis Res Ther. 2010;12:R81.CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Filková M, Aradi B, Senolt L, Ospelt C, Vettori S, Mann H, Gay S, et al. Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. Ann Rheum Dis. 2014;73(10):1898–904.CrossRefPubMed Filková M, Aradi B, Senolt L, Ospelt C, Vettori S, Mann H, Gay S, et al. Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis. Ann Rheum Dis. 2014;73(10):1898–904.CrossRefPubMed
11.
Zurück zum Zitat Chen ZZ, Zhang XD, Chen Y, Wu YB. The role of circulating miR-146a in patients with rheumatoid arthritis treated by Tripterygium wilfordii Hook F. Medicine (Baltimore). 2017;96(20):e6775.CrossRef Chen ZZ, Zhang XD, Chen Y, Wu YB. The role of circulating miR-146a in patients with rheumatoid arthritis treated by Tripterygium wilfordii Hook F. Medicine (Baltimore). 2017;96(20):e6775.CrossRef
12.
Zurück zum Zitat Long L, Yu P, Liu Y, Wang S, Li R, et al. Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. Clin Dev Immunol. 2013;2013:296139.CrossRefPubMedPubMedCentral Long L, Yu P, Liu Y, Wang S, Li R, et al. Upregulated microRNA-155 expression in peripheral blood mononuclear cells and fibroblast-like synoviocytes in rheumatoid arthritis. Clin Dev Immunol. 2013;2013:296139.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Miao CG, Yang YY, He X, et al. New advances of microRNAs in the pathogenesis of rheumatoid arthritis, with a focus on the crosstalk between DNA methylation and the microRNA machinery. Cell Signal. 2013;25:1118–25.CrossRefPubMed Miao CG, Yang YY, He X, et al. New advances of microRNAs in the pathogenesis of rheumatoid arthritis, with a focus on the crosstalk between DNA methylation and the microRNA machinery. Cell Signal. 2013;25:1118–25.CrossRefPubMed
14.
Zurück zum Zitat Vicente R, Noel D, Pers YM, Apparailly F, Jorgensen C. Deregulation and therapeutic potential of microRNAs in arthritic diseases. Nat Rev Rheumatol. 2016;12:211–20.CrossRefPubMed Vicente R, Noel D, Pers YM, Apparailly F, Jorgensen C. Deregulation and therapeutic potential of microRNAs in arthritic diseases. Nat Rev Rheumatol. 2016;12:211–20.CrossRefPubMed
15.
Zurück zum Zitat Song Z, Li G. Role of specific microRNAs in regulation of vascular smooth muscle cell differentiation and the response to injury. J Cardiovasc Transl Res. 2010;3:246–50.CrossRefPubMedPubMedCentral Song Z, Li G. Role of specific microRNAs in regulation of vascular smooth muscle cell differentiation and the response to injury. J Cardiovasc Transl Res. 2010;3:246–50.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Kuehbacher A, Urbich C, Dimmeler S. Targeting microRNA expression to regulate angiogenesis. Trends Pharmacol Sci. 2008;29:12–5.CrossRefPubMed Kuehbacher A, Urbich C, Dimmeler S. Targeting microRNA expression to regulate angiogenesis. Trends Pharmacol Sci. 2008;29:12–5.CrossRefPubMed
17.
Zurück zum Zitat Chistiakov DA, Sobenin IA, Orekhov AN, Bobryshev YV. Human miR-221/222 in physiological and atherosclerotic vascular remodeling. Biomed Res Int. 2015;2015:354517.CrossRefPubMedPubMedCentral Chistiakov DA, Sobenin IA, Orekhov AN, Bobryshev YV. Human miR-221/222 in physiological and atherosclerotic vascular remodeling. Biomed Res Int. 2015;2015:354517.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Rippe C, Blimline M, Magerko KA, et al. microRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp Gerontol. 2012;47:45–51.CrossRefPubMed Rippe C, Blimline M, Magerko KA, et al. microRNA changes in human arterial endothelial cells with senescence: relation to apoptosis, eNOS and inflammation. Exp Gerontol. 2012;47:45–51.CrossRefPubMed
19.
Zurück zum Zitat Stenmark KR, Yeager ME, El Kasmi KC, et al. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol. 2013;75:23–47.CrossRefPubMed Stenmark KR, Yeager ME, El Kasmi KC, et al. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol. 2013;75:23–47.CrossRefPubMed
20.
Zurück zum Zitat Yang S, Yang Y. Downregulation of microRNA221 decreases migration and invasion in fibroblast-like synoviocytes in rheumatoid arthritis. Mol Med Rep. 2015;12:2395–401.CrossRefPubMed Yang S, Yang Y. Downregulation of microRNA221 decreases migration and invasion in fibroblast-like synoviocytes in rheumatoid arthritis. Mol Med Rep. 2015;12:2395–401.CrossRefPubMed
21.
Zurück zum Zitat Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.CrossRefPubMed Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62(9):2569–81.CrossRefPubMed
22.
Zurück zum Zitat Prevoo ML, van ‘t Hof MA MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8.CrossRefPubMed Prevoo ML, van ‘t Hof MA MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–8.CrossRefPubMed
23.
Zurück zum Zitat Pincus T, Yazici Y. Bergman M. Development of a multi-dimensional health assessment questionnaire (MD-HAQ) for the infrastructure of standard clinical care. Clin Exp Rheumatol. 2005;23(Suppl 39):S19–28.PubMed Pincus T, Yazici Y. Bergman M. Development of a multi-dimensional health assessment questionnaire (MD-HAQ) for the infrastructure of standard clinical care. Clin Exp Rheumatol. 2005;23(Suppl 39):S19–28.PubMed
24.
Zurück zum Zitat Talaat RM, El-Bassiouny AI, Osman AM, Yossif M, Charmy R, Al-Sherbiny MM. Cytokine secretion profile associated with periportal fibrosis in S. mansoni-infected Egyptian patients. Parasitol Res. 2007;101:289–99.CrossRefPubMed Talaat RM, El-Bassiouny AI, Osman AM, Yossif M, Charmy R, Al-Sherbiny MM. Cytokine secretion profile associated with periportal fibrosis in S. mansoni-infected Egyptian patients. Parasitol Res. 2007;101:289–99.CrossRefPubMed
26.
Zurück zum Zitat Duroux-Richard I, Jorgensen C, Apparailly F. miRNAs and rheumatoid arthritis—promising novel biomarkers. Swiss Med Wkly. 2011;141:w13175.PubMed Duroux-Richard I, Jorgensen C, Apparailly F. miRNAs and rheumatoid arthritis—promising novel biomarkers. Swiss Med Wkly. 2011;141:w13175.PubMed
27.
Zurück zum Zitat Zhu S, Pan W, Song X, et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB 2, TAB 3 and IKK-α. Nat Med. 2012;18(7):1077–86.CrossRefPubMed Zhu S, Pan W, Song X, et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB 2, TAB 3 and IKK-α. Nat Med. 2012;18(7):1077–86.CrossRefPubMed
28.
Zurück zum Zitat O’Connell RM, Kahn D, Gibson WS, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33:607–19.CrossRefPubMedPubMedCentral O’Connell RM, Kahn D, Gibson WS, et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity. 2010;33:607–19.CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Baxter D, McInnes IB, Kurowska-Stolarska M. Novel regulatory mechanisms in inflammatory arthritis: a role for microRNA. Immunol Cell Biol. 2012;90:288–92.CrossRefPubMed Baxter D, McInnes IB, Kurowska-Stolarska M. Novel regulatory mechanisms in inflammatory arthritis: a role for microRNA. Immunol Cell Biol. 2012;90:288–92.CrossRefPubMed
30.
Zurück zum Zitat Jimenez SA, Piera-Velazquez S. Potential role of human-specific genes, human specific microRNAs and human-specific non-coding regulatory RNAs in the pathogenesis of systemic sclerosis and Sjogren’s syndrome. Autoimmun Rev. 2013;12:1046–51.CrossRefPubMedPubMedCentral Jimenez SA, Piera-Velazquez S. Potential role of human-specific genes, human specific microRNAs and human-specific non-coding regulatory RNAs in the pathogenesis of systemic sclerosis and Sjogren’s syndrome. Autoimmun Rev. 2013;12:1046–51.CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Bottini N, Firestein GS. Epigenetics in rheumatoid arthritis: a primer for rheumatologists. Curr Rheumatol Rep. 2013;15(11):372.CrossRefPubMed Bottini N, Firestein GS. Epigenetics in rheumatoid arthritis: a primer for rheumatologists. Curr Rheumatol Rep. 2013;15(11):372.CrossRefPubMed
34.
Zurück zum Zitat Reveille JD. Genetic studies in the rheumatic diseases: present status and implications for the future. J Rheumatol Suppl. 2005;72:10–3.PubMed Reveille JD. Genetic studies in the rheumatic diseases: present status and implications for the future. J Rheumatol Suppl. 2005;72:10–3.PubMed
35.
Zurück zum Zitat Zhou Q, Haupt S, Kreuzer JT, et al. Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1265–74.CrossRefPubMed Zhou Q, Haupt S, Kreuzer JT, et al. Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1265–74.CrossRefPubMed
36.
Zurück zum Zitat Churov AV, Oleinik EK, Knip M. MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun Rev. 2015;14(11):1029–37.CrossRefPubMed Churov AV, Oleinik EK, Knip M. MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential. Autoimmun Rev. 2015;14(11):1029–37.CrossRefPubMed
37.
Zurück zum Zitat Kim T-H, Choi SJ, Lee YH, Song GG, Ji JD. Gene expression profile predicting the response to anti-TNF treatment in patients with rheumatoid arthritis; analysis of GEO datasets. Joint Bone Spine. 2014;81(4):325–30.CrossRefPubMed Kim T-H, Choi SJ, Lee YH, Song GG, Ji JD. Gene expression profile predicting the response to anti-TNF treatment in patients with rheumatoid arthritis; analysis of GEO datasets. Joint Bone Spine. 2014;81(4):325–30.CrossRefPubMed
39.
Zurück zum Zitat Ruedel A, Dietrich P, Schubert T, Hofmeister S, Hellerbrand C, Bosserhoff AK. Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts. Int J Clin Exp Pathol. 2015;8(6):6607–16.PubMedPubMedCentral Ruedel A, Dietrich P, Schubert T, Hofmeister S, Hellerbrand C, Bosserhoff AK. Expression and function of microRNA-188-5p in activated rheumatoid arthritis synovial fibroblasts. Int J Clin Exp Pathol. 2015;8(6):6607–16.PubMedPubMedCentral
40.
Zurück zum Zitat Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10:R101.CrossRefPubMedPubMedCentral Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EK. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10:R101.CrossRefPubMedPubMedCentral
44.
Zurück zum Zitat Chen CF, Huang J, Li H, Zhang C, Huang X, Tong G, et al. microRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1. Gene. 2015;565:246–51.CrossRefPubMed Chen CF, Huang J, Li H, Zhang C, Huang X, Tong G, et al. microRNA-221 regulates endothelial nitric oxide production and inflammatory response by targeting adiponectin receptor 1. Gene. 2015;565:246–51.CrossRefPubMed
45.
Zurück zum Zitat Migeon BR. Females are mosaics: X inactivation and sex differences in disease. New York: Oxford University Press, Inc.; 2007. Migeon BR. Females are mosaics: X inactivation and sex differences in disease. New York: Oxford University Press, Inc.; 2007.
46.
Zurück zum Zitat Ozcelik T. X chromosome inactivation and female predisposition to autoimmunity. Clin Rev Allergy Immunol. 2008;34:348–51.CrossRefPubMed Ozcelik T. X chromosome inactivation and female predisposition to autoimmunity. Clin Rev Allergy Immunol. 2008;34:348–51.CrossRefPubMed
47.
Zurück zum Zitat Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2010;24:733–45.CrossRefPubMed Carmona L, Cross M, Williams B, Lassere M, March L. Rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2010;24:733–45.CrossRefPubMed
48.
Zurück zum Zitat Kukurba KR, Parsana P, Balliu B, Smith K, Zappala Z, Knowles DA, et al. Impact of the X Chromosome and sex on regulatory variation. Genome Res. 2016;26:768–77.CrossRefPubMedPubMedCentral Kukurba KR, Parsana P, Balliu B, Smith K, Zappala Z, Knowles DA, et al. Impact of the X Chromosome and sex on regulatory variation. Genome Res. 2016;26:768–77.CrossRefPubMedPubMedCentral
49.
Zurück zum Zitat Khalifa O, Pers YM, Ferreira R, Sénéchal A, et al. X-linked miRNAs associated with gender differences in rheumatoid arthritis. Int J Mol Sci. 2016;17(11):1852.CrossRefPubMedCentral Khalifa O, Pers YM, Ferreira R, Sénéchal A, et al. X-linked miRNAs associated with gender differences in rheumatoid arthritis. Int J Mol Sci. 2016;17(11):1852.CrossRefPubMedCentral
50.
Zurück zum Zitat Teixeira AL, Ferreira M, Silva J, Gomes M, et al. Higher circulating expression Levels of miR-221 associated with poor overall survival in renal cell carcinoma patients. Tumour Biol. 2014;35(5):4057–66.CrossRefPubMed Teixeira AL, Ferreira M, Silva J, Gomes M, et al. Higher circulating expression Levels of miR-221 associated with poor overall survival in renal cell carcinoma patients. Tumour Biol. 2014;35(5):4057–66.CrossRefPubMed
51.
Zurück zum Zitat El-Garem H, Ammer A, Shehab H, Shaker O, et al. Circulating microRNA, miR-122 and miR-221 signature in Egyptian patients with chronic hepatitis C related hepatocellular carcinoma. World J Hepatol. 2014;6(11):818–24.CrossRefPubMedPubMedCentral El-Garem H, Ammer A, Shehab H, Shaker O, et al. Circulating microRNA, miR-122 and miR-221 signature in Egyptian patients with chronic hepatitis C related hepatocellular carcinoma. World J Hepatol. 2014;6(11):818–24.CrossRefPubMedPubMedCentral
Metadaten
Titel
Upregulation of miR-221/222 expression in rheumatoid arthritis (RA) patients: correlation with disease activity
verfasst von
Amira S. Abo ElAtta
Yasser B. M. Ali
Iman H. Bassyouni
Roba M. Talaat
Publikationsdatum
21.08.2018
Verlag
Springer International Publishing
Erschienen in
Clinical and Experimental Medicine / Ausgabe 1/2019
Print ISSN: 1591-8890
Elektronische ISSN: 1591-9528
DOI
https://doi.org/10.1007/s10238-018-0524-3

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