Expression profile and diagnostic value of circRNAs in peripheral blood from patients with systemic lupus erythematosus

Luo,Qing; Li,Xue; Fu,Biqi; Zhang,Lu; Fang,Le; Qing,Cheng; Guo,Yang; Huang,Zikun; Li,Junming

doi:10.3892/mmr.2020.11639

Expression profile and diagnostic value of circRNAs in peripheral blood from patients with systemic lupus erythematosus

Authors:
- Qing Luo
- Xue Li
- Biqi Fu
- Lu Zhang
- Le Fang
- Cheng Qing
- Yang Guo
- Zikun Huang
- Junming Li
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Affiliations: Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Rheumatology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 710065, P.R. China, Department of Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Blood Transfusion, 521 Hospital of Ordnance Industry, Xi'an, Shanxi 710065, P.R. China, Department of Intensive Care Unit, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: November 2, 2020 https://doi.org/10.3892/mmr.2020.11639
Article Number: 1
Copyright: © Luo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Circular RNAs (circRNAs) have gained attention due to their performance in disease diagnosis. However, the characteristics of circRNAs in peripheral blood from patients with systemic lupus erythematosus (SLE) remain unknown. Therefore, the aim of the present study was to determine the expression profile and diagnostic potential of circRNAs in peripheral blood from patients with SLE. The global circRNA expression in the peripheral blood of patients with SLE and healthy controls (HCs) was detected using a circRNA microarray. Then, the expression levels of three upregulated circRNAs were selected for further validation by reverse transcription‑quantitative PCR (RT‑qPCR) in a training set. Moreover, the diagnostic value of these circRNAs was assessed by constructing a receiver operating characteristic curve, and then verified in a blind testing set. In total, 1,566 circRNAs were identified to be dysregulated between patients with SLE and HCs (≥2 fold change, P<0.05). Furthermore, the RT‑qPCR results were consistent with the microarray data, in that all three selected circRNAs, hsa_circ_0082688, hsa_circ_0082689 and hsa_circ_0008675, were significantly upregulated in patients with SLE (P<0.05). Results from the training set demonstrated that the combination of hsa_circ_0082688‑hsa_circ_0082689 may provide the most beneficial diagnostic potential. Moreover, the blind test results indicated that the combination model of hsa_circ_0082688‑hsa_circ_0082689 could effectively discriminate between patients with SLE from patients with rheumatoid arthritis and HCs, with a sensitivity of 91.30%, a specificity of 78.57% and an accuracy of 82.28%. Moreover, the combination model of hsa_circ_0082688‑hsa_circ_0082689 + anti‑dsDNA could more effectively discriminated the SLE group from the control groups, with a sensitivity of 95.65%, a specificity of 100.00% and an accuracy of 98.73%. In addition, correlation analysis results suggested that all three circRNAs in patients with SLE did not correlate with the SLE disease activity index. In conclusion, the expression levels of hsa_circ_0082688‑hsa_circ_0082689 may serve as potential biomarkers for SLE diagnosis.

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1	Tsokos GC: Systemic lupus erythematosus. N Engl J Med. 365:2110–2121. 2011. View Article : Google Scholar : PubMed/NCBI
2	Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P and Khamashta MA: Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: A systematic review. Ann Rheum Dis. 69:20–28. 2010. View Article : Google Scholar : PubMed/NCBI
3	Chang NH, Li TT, Kim JJ, Landolt-Marticorena C, Fortin PR, Gladman DD, Urowitz MB and Wither JE: Interferon alpha induces altered transitional B cell signaling and function in systemic lupus erythematosus. J Autoimmun. 58:100–110. 2015. View Article : Google Scholar : PubMed/NCBI
4	Zhao M, Liu S, Luo S, Wu H, Tang M, Cheng W, Zhang Q, Zhang P, Yu X, Xia Y, et al: DNA methylation and mRNA and microRNA expression of SLE CD4+ T cells correlate with disease phenotype. J Autoimmun. 54:127–136. 2014. View Article : Google Scholar : PubMed/NCBI
5	O'Gorman WE, Hsieh EW, Savig ES, Gherardini PF, Hernandez JD, Hansmann L, Balboni IM, Utz PJ, Bendall SC, Fantl WJ, et al: Single-cell systems-level analysis of human Toll-like receptor activation defines a chemokine signature in patients with systemic lupus erythematosus. J Allergy Clin Immunol. 136:1326–1336. 2015. View Article : Google Scholar : PubMed/NCBI
6	Lech M, Kantner C, Kulkarni OP, Ryu M, Vlasova E, Heesemann J, Anz D, Endres S, Kobayashi KS, Flavell RA, et al: Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus. Ann Rheum Dis. 70:2207–2217. 2011. View Article : Google Scholar : PubMed/NCBI
7	Huang Z, Shi Y, Cai B, Wang L, Wu Y, Ying B, Qin L, Hu C and Li Y: MALDI-TOF MS combined with magnetic beads for detecting serum protein biomarkers and establishment of boosting decision tree model for diagnosis of systemic lupus erythematosus. Rheumatology (Oxford). 48:626–631. 2009. View Article : Google Scholar : PubMed/NCBI
8	Ferreira TAR, de Andrade HM, de Pádua PM, Carvalho MDG, Pires SDF, Oliveira IHR, Lima BSS, Fialho Júnior LC, Cicarini WB, Chapeourouge DA, et al: Identification of potential biomarkers for systemic lupus erythematosus diagnosis using two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry. Autoimmunity. 50:247–256. 2017. View Article : Google Scholar : PubMed/NCBI
9	Wu GC, Li J, Leng RX, Li XP, Li XM, Wang DG, Pan HF and Ye DQ: Identification of long non-coding RNAs GAS5, linc0597 and lnc-DC in plasma as novel biomarkers for systemic lupus erythematosus. Oncotarget. 8:23650–23663. 2017. View Article : Google Scholar : PubMed/NCBI
10	Barrett SP, Wang PL and Salzman J: Circular RNA biogenesis can proceed through an exon-containing lariat precursor. Elife. 4:e075402015. View Article : Google Scholar : PubMed/NCBI
11	Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L, et al: Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 22:256–264. 2015. View Article : Google Scholar : PubMed/NCBI
12	Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF and Sharpless NE: Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 19:141–157. 2013. View Article : Google Scholar : PubMed/NCBI
13	Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al: Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495:333–338. 2013. View Article : Google Scholar : PubMed/NCBI
14	Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK and Kjems J: Natural RNA circles function as efficient microRNA sponges. Nature. 495:384–388. 2013. View Article : Google Scholar : PubMed/NCBI
15	Jeck WR and Sharpless NE: Detecting and characterizing circular RNAs. Nat Biotechnol. 32:453–461. 2014. View Article : Google Scholar : PubMed/NCBI
16	Burd CE, Jeck WR, Liu Y, Sanoff HK, Wang Z and Sharpless NE: Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet. 6:e10012332010. View Article : Google Scholar : PubMed/NCBI
17	Hansen TB, Kjems J and Damgaard CK: Circular RNA and miR-7 in cancer. Cancer Res. 73:5609–5612. 2013. View Article : Google Scholar : PubMed/NCBI
18	Li F, Zhang L, Li W, Deng J, Zheng J, An M, Lu J and Zhou Y: Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/β-catenin pathway. Oncotarget. 6:6001–6013. 2015. View Article : Google Scholar : PubMed/NCBI
19	Ouyang Q, Wu J, Jiang Z, Zhao J, Wang R, Lou A, Zhu D, Shi GP and Yang M: Microarray expression profile of circular RNAs in peripheral blood mononuclear cells from rheumatoid arthritis patients. Cell Physiol Biochem. 42:651–659. 2017. View Article : Google Scholar : PubMed/NCBI
20	Lin X, Lo HC, Wong DT and Xiao X: Noncoding RNAs in human saliva as potential disease biomarkers. Front Genet. 6:1752015. View Article : Google Scholar : PubMed/NCBI
21	Memczak S, Papavasileiou P, Peters O and Rajewsky N: Identification and characterization of circular RNAs As a new class of putative biomarkers in human blood. PLoS One. 10:e01412142015. View Article : Google Scholar : PubMed/NCBI
22	You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, Akbalik G, Wang M, Glock C, Quedenau C, et al: Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci. 18:603–610. 2015. View Article : Google Scholar : PubMed/NCBI
23	Salzman J, Chen RE, Olsen MN, Wang PL and Brown PO: Cell-type specific features of circular RNA expression. PLoS Genet. 9:e10037772013. View Article : Google Scholar : PubMed/NCBI
24	Zhao Z, Li X, Jian D, Hao P, Rao L and Li M: Hsa_circ_0054633 in peripheral blood can be used as a diagnostic biomarker of pre-diabetes and type 2 diabetes mellitus. Acta Diabetol. 54:237–245. 2017. View Article : Google Scholar : PubMed/NCBI
25	Zhao Z, Li X, Gao C, Jian D, Hao P, Rao L and Li M: Peripheral blood circular RNA hsa_circ_0124644 can be used as a diagnostic biomarker of coronary artery disease. Sci Rep. 7:399182017. View Article : Google Scholar : PubMed/NCBI
26	Luo Q, Zhang L, Li X, Fu B, Guo Y, Huang Z and Li J: Identification of circular RNAs hsa_circ_0044235 and hsa_circ_0068367 as novel biomarkers for systemic lupus erythematosus. Int J Mol Med. 44:1462–1472. 2019.PubMed/NCBI
27	Hochberg MC: Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40:17251997. View Article : Google Scholar : PubMed/NCBI
28	Bombardier C, Gladman DD, Urowitz MB, Caron D and Chang CH: Derivation of the SLEDAI. A disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum. 35:630–640. 1992. View Article : Google Scholar : PubMed/NCBI
29	Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al: The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthr Rhuem. 31:315–324. 1988. View Article : Google Scholar
30	Luo Q, Li X, Xu C, Zeng L, Ye J, Guo Y, Huang Z and Li J: Integrative analysis of long non-coding RNAs and messenger RNA expression profiles in systemic lupus erythematosus. Mol Med Rep. 17:3489–3496. 2018.PubMed/NCBI
31	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
32	Luo Q, Zhang L, Fang L, Fu B, Guo Y, Huang Z and Li J: Circular RNAs hsa_circ_0000479 in peripheral blood mononuclear cells as novel biomarkers for systemic lupus erythematosus. Autoimmunity. 53:167–176. 2020. View Article : Google Scholar : PubMed/NCBI
33	Soliman S and Mohan C: Lupus nephritis biomarkers. Clin Immunol. 185:10–20. 2017. View Article : Google Scholar : PubMed/NCBI
34	Stypinska B and Paradowska-Gorycka A: Cytokines and MicroRNAs as candidate biomarkers for systemic lupus erythematosus. Int J Mol Sci. 16:24194–24218. 2015. View Article : Google Scholar : PubMed/NCBI
35	Wu Y, Zhang F, Ma J, Zhang X, Wu L, Qu B, Xia S, Chen S, Tang Y and Shen N: Association of large intergenic noncoding RNA expression with disease activity and organ damage in systemic lupus erythematosus. Arthritis Res Ther. 17:1312015. View Article : Google Scholar : PubMed/NCBI
36	Guo JN, Li J, Zhu CL, Feng WT, Shao JX, Wan L, Huang MD and He JD: Comprehensive profile of differentially expressed circular RNAs reveals that hsa_circ_0000069 is upregulated and promotes cell proliferation, migration, and invasion in colorectal cancer. Onco Targets Ther. 9:7451–7458. 2016. View Article : Google Scholar : PubMed/NCBI
37	Liang D and Wilusz JE: Short intronic repeat sequences facilitate circular RNA production. Genes Dev. 28:2233–2247. 2014. View Article : Google Scholar : PubMed/NCBI
38	Ouyang Q, Huang Q, Jiang Z, Zhao J, Shi GP and Yang M: Using plasma circRNA_002453 as a novel biomarker in the diagnosis of lupus nephritis. Mol Immunol. 101:531–538. 2018. View Article : Google Scholar : PubMed/NCBI
39	Zhang MY, Wang JB, Zhu ZW, Li LJ, Liu RS, Yang XK, Leng RX, Li XM, Pan HF and Ye DQ: Differentially expressed circular RNAs in systemic lupus erythematosus and their clinical significance. Biomed Pharmacother. 107:1720–1727. 2018. View Article : Google Scholar : PubMed/NCBI
40	Li S, Zhang J, Tan X, Deng J, Li Y, Piao Y, Li C, Yang W, Mo W, Sun J, et al: Microarray expression profile of circular RNAs and mRNAs in children with systemic lupus erythematosus. Clin Rheumatol. 38:1339–1350. 2019. View Article : Google Scholar : PubMed/NCBI
41	Yi F, Hao Y, Chong X and Zhong W: Overexpression of microRNA-506-3p aggravates the injury of vascular endothelial cells in patients with hypertension by downregulating Beclin1 expression. Exp Ther Med. 15:2844–2850. 2018.PubMed/NCBI
42	Pan Q, Gao C, Chen Y, Feng Y, Liu WJ and Liu HF: Update on the role of autophagy in systemic lupus erythematosus: A novel therapeutic target. Biomed Pharmacother. 71:190–193. 2015. View Article : Google Scholar : PubMed/NCBI
43	Liang J, Xu L, Zhou F, Liu AM, Ge HX, Chen YY and Tu M: MALAT1/miR-127-5p regulates osteopontin (OPN)-mediated proliferation of human chondrocytes through PI3K/Akt pathway. J Cell Biochem. 119:431–439. 2018. View Article : Google Scholar : PubMed/NCBI
44	Chen H, Shi B, Feng X, Kong W, Chen W, Geng L, Chen J, Liu R, Li X, Chen W, et al: Leptin and neutrophil-activating peptide 2 promote mesenchymal stem cell senescence through activation of the phosphatidylinositol 3-kinase/Akt pathway in patients with systemic lupus erythematosus. Arthritis Rheumatol. 67:2383–2393. 2015. View Article : Google Scholar : PubMed/NCBI
45	Navarro-Quiroz E, Pacheco-Lugo L, Navarro-Quiroz R, Lorenzi H, España-Puccini P, Díaz-Olmos Y, Almendrales L, Olave V, Gonzalez-Torres H, Diaz-Perez A, et al: Profiling analysis of circulating microRNA in peripheral blood of patients with class IV lupus nephritis. PLoS One. 12:e01879732017. View Article : Google Scholar : PubMed/NCBI