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Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus

  • Authors:
    • Xinyu Shi
    • Lulu Ye
    • Shuqi Xu
    • Gangqiang Guo
    • Ziyi Zuo
    • Mengke Ye
    • Lejiang Zhu
    • Baoqing Li
    • Xiangyang Xue
    • Qiaoai Lin
    • Xiaokai Ding
  • View Affiliations / Copyright

    Affiliations: Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Laboratory Medicine, Anqing Petrochemical Hospital, Anqing, Anhui 246000, P.R. China, First Clinical College, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Nephrology, Wenzhou Central Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Laboratory Medicine, Second Affiliated Hospital & Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Nephrology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
    Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 841-849
    |
    Published online on: May 21, 2020
       https://doi.org/10.3892/mmr.2020.11166
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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder; however, the pathogenesis is not fully understood. Accumulating evidence suggested an important role of microRNAs (miRNA/miR) in autoimmunity. The present study aimed therefore to determine the miRNA expression patterns in the B cells from the peripheral blood of 66 patients with SLE and 10 healthy controls (HCs) by using an Affymetrix GeneChip® miRNA 2.0 array. In addition, next‑generation sequencing was used to obtain the peripheral blood mononuclear cell (PBMC) miRNA profiles from three patients with SLE and three HCs. Candidate miRNAs that were considered to contribute to the pathogenesis of SLE were obtained based on the intersection of miRNA profiles. The analysis revealed a significant downregulation in miR‑29a expression levels in B cells from patients with SLE, which was subsequently verified using reverse transcription‑quantitative PCR. Based on these results, the expression pattern of miR‑29a in SLE was further investigated and its role in the hyperactivity of B cells was determined. miR‑29a inhibitors and mimics were transfected into PBMCs obtained from HCs and patients with SLE, and an ELISA was used to demonstrate that miR‑29a inhibition increased the production of IgG. Bioinformatics analysis predicted Crk‑like protein (CRKL) as a target gene of miR‑29a in patients with SLE. Therefore, CRKL expression levels were compared between patients with SLE and HCs by using western blotting, and its direct transcriptional regulation by miR‑29a was determined using a dual‑luciferase reporter assay. Low expression levels of miR‑29a were revealed to upregulate the expression levels of CRKL in B cells, and the protein expression levels of CRKL in patients with SLE were significantly upregulated compared with the HCs. In conclusion, the results from the present study suggested that miR‑29a may affect IgG antibody secretion in B cells by regulating CRKL, thereby contributing to the development and progression of SLE, which offers a novel candidate target for treatment.
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1 

Frieri M: Mechanisms of disease for the clinician: Systemic lupus erythematosus. Ann Allerg Asthma Im. 110:228–232. 2013. View Article : Google Scholar

2 

Ziegelasch M, van Delft MA, Wallin P, Skogh T, Magro-Checa C, Steup-Beekman GM, Trouw LA, Kastbom A and Sjöwall C: Antibodies against carbamylated proteins and cyclic citrullinated peptides in systemic lupus erythematosus: Results from two well-defined European cohorts. Arthritis Res Ther. 18:2892016. View Article : Google Scholar : PubMed/NCBI

3 

Guo G, Wang H, Shi X, Ye L, Wu K, Lin K, Ye S, Li B, Zhang H, Lin Q, et al: NovelmiRNA-25 inhibits AMPD2 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and represents a promising novel biomarker. J Transl Med. 16:3702018. View Article : Google Scholar : PubMed/NCBI

4 

Jeltsch-David H and Muller S: Neuropsychiatric systemic lupus erythematosus: Pathogenesis and biomarkers. Nat Rev Neurol. 10:579–596. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Bernatsky S, Joseph L, Boivin JF, Gordon C, Urowitz M, Gladman D, Fortin PR, Ginzler E, Bae SC, Barr S, et al: The relationship between cancer and medication exposures in systemic lupus erythaematosus: A case-cohort study. Ann Rheum Dis. 67:74–79. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Baudino L, Yoshinobu K, Morito N, Santiago-Raber ML and Izui S: Role of endogenous retroviruses in murine SLE. Autoimmun Rev. 10:27–34. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Luo S, Liu Y, Liang G, Zhao M, Wu H, Liang Y, Qiu X, Tan Y, Dai Y, Yung S, et al: The role of microRNA-1246 in the regulation of B cell activation and the pathogenesis of systemic lupus erythematosus. Clin Epigenetics. 7:242015. View Article : Google Scholar : PubMed/NCBI

8 

Yu F, Haas M, Glassock R and Zhao MH: Redefining lupus nephritis: Clinical implications of pathophysiologic subtypes. Nat Rev Nephrol. 13:483–495. 2017. View Article : Google Scholar : PubMed/NCBI

9 

Xie HH, Shen H, Zhang L, Cui MY, Xia LP and Lu J: Elevated serum interleukin-34 level in patients with systemic lupus erythematosus is associated with disease activity. Sci Rep. 8:34622018. View Article : Google Scholar : PubMed/NCBI

10 

Zhou B, Zuo XX, Li YS, Gao SM, Dai XD, Zhu HL and Luo H: Integration of microRNA and mRNA expression profiles in the skin of systemic sclerosis patients. Sci Rep. 7:428992017. View Article : Google Scholar : PubMed/NCBI

11 

Luo Q, Liu J, Fu B, Zhang L, Guo Y, Huang Z and Li J: Circular RNAs Hsa_circ_0002715 and Hsa_circ_0035197 in peripheral blood are novel potential biomarkers for new-onset rheumatoid arthritis. Dis Markers. 2019:20731392019. View Article : Google Scholar : PubMed/NCBI

12 

He L and Hannon GJ: MicroRNAs: Small RNAs with a big role in gene regulation. Nat Rev Genet. 5:522–531. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Xiao C and Rajewsky K: microrna control in the immune system: Basic principles. Cell. 136:26–36. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Ma X and Liu Q: MicroRNAs in the pathogenesis of systemic lupus erythematosus. Int J Rheum Dis. 16:115–121. 2013. View Article : Google Scholar : PubMed/NCBI

15 

de Yébenes VG, Bartolomé-Izquierdo N and Ramiro AR: Regulation of B-cell development and function by microRNAs. Immunol Rev. 253:25–39. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Hong Y, Wu J, Zhao J, Wang H, Liu Y, Chen T, Kan X, Tao Q, Shen X, Yan K and Zhai Z: miR-29b and miR-29c are involved in Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid dendritic cells. PLoS One. 8:e699262013. View Article : Google Scholar : PubMed/NCBI

17 

Monteleone K, Selvaggi C, Cacciotti G, Falasca F, Mezzaroma I, D'Ettorre G, Turriziani O, Vullo V, Antonelli G and Scagnolari C: MicroRNA-29 family expression and its relation to antiviral immune response and viro-immunological markers in HIV-1-infected patients. BMC Infect Dis. 15:512015. View Article : Google Scholar : PubMed/NCBI

18 

Sun XJ, Liu BY, Yan S, Jiang TH, Cheng HQ, Jiang HS, Jiang HS, Cao Y and Mao AW: MicroRNA-29a promotes pancreatic cancer growth by inhibiting tristetraprolin. Cell Physiol Biochem. 37:707–718. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Liston A, Papadopoulou AS, Danso-Abeam D and Dooley J: MicroRNA-29 in the adaptive immune system: Setting the threshold. Cell Mol Life Sci. 69:3533–3541. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Wang X, Zhang C, Wu Z, Chen Y and Shi W: CircIBTK inhibits DNA demethylation and activation of AKT signaling pathway via miR-29b in peripheral blood mononuclear cells in systemic lupus erythematosus. Arthritis Res Ther. 20:1182018. View Article : Google Scholar : PubMed/NCBI

21 

Ahluwalia JK, Khan SZ, Soni K, Rawat P, Gupta A, Hariharan M, Scaria V, Lalwani M, Pillai B, Mitra D and Brahmachari SK: Human cellular microRNA hsa-miR-29a interferes with viral nef protein expression and HIV-1 replication. Retrovirology. 5:1172008. View Article : Google Scholar : PubMed/NCBI

22 

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

23 

Maugeri M, Barbagallo D, Barbagallo C, Banelli B, Di Mauro S, Purrello F, Magro G, Ragusa M, Di Pietro C, Romani M and Purrello M: Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma. Oncotarget. 7:83330–83341. 2016. View Article : Google Scholar : PubMed/NCBI

24 

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

25 

Lipsky PE: Systemic lupus erythematosus: An autoimmune disease of B cell hyperactivity. Nat Immunol. 2:764–766. 2001. View Article : Google Scholar : PubMed/NCBI

26 

Sherer Y, Gorstein A, Fritzler MJ and Shoenfeld Y: Autoantibody explosion in systemic lupus erythematosus: More than 100 different antibodies found in SLE patients. Semin Arthritis Rheum. 34:501–537. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Zhao M, Liu Q, Liang G, Wang L, Luo S, Tang Q, Zhao H, Su Y, Yung S, Chan TM and Lu Q: E4BP4 overexpression: A protective mechanism in CD4+ T cells from SLE patients. J Autoimmun. 41:152–160. 2013. View Article : Google Scholar : PubMed/NCBI

28 

Zhao JJ, Lin J, Lwin T, Yang H, Guo J, Kong W, Dessureault S, Moscinski LC, Rezania D, Dalton WS, et al: MicroRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood. 115:2630–2639. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Liu M, Zeng X, Lu YX, Mo YJ, Liao TH, Gan C and Lu XQ: Study on molecular mechanism of MiRNA-29a in promoting proliferation and invasion of non-small-cell lung cancer by inhibiting MTSS1. Eur Rev Med Pharmacol Sci. 22:5531–5538. 2018.PubMed/NCBI

30 

Aiello FB, Guszczynski T, Li W, Hixon JA, Jiang Q, Hodge DL, Massignan T, Di Lisio C, Merchant A, Procopio AD, et al: IL-7-induced phosphorylation of the adaptor Crk-like and other targets. Cell Signal. 47:131–141. 2018. View Article : Google Scholar : PubMed/NCBI

31 

Jankowski A, Zhu P and Marshall JG: Capture of an activated receptor complex from the surface of live cells by affinity receptor chromatography. Anal Biochem. 380:235–248. 2008. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Shi X, Ye L, Xu S, Guo G, Zuo Z, Ye M, Zhu L, Li B, Xue X, Lin Q, Lin Q, et al: Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus. Mol Med Rep 22: 841-849, 2020.
APA
Shi, X., Ye, L., Xu, S., Guo, G., Zuo, Z., Ye, M. ... Ding, X. (2020). Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus. Molecular Medicine Reports, 22, 841-849. https://doi.org/10.3892/mmr.2020.11166
MLA
Shi, X., Ye, L., Xu, S., Guo, G., Zuo, Z., Ye, M., Zhu, L., Li, B., Xue, X., Lin, Q., Ding, X."Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus". Molecular Medicine Reports 22.2 (2020): 841-849.
Chicago
Shi, X., Ye, L., Xu, S., Guo, G., Zuo, Z., Ye, M., Zhu, L., Li, B., Xue, X., Lin, Q., Ding, X."Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus". Molecular Medicine Reports 22, no. 2 (2020): 841-849. https://doi.org/10.3892/mmr.2020.11166
Copy and paste a formatted citation
x
Spandidos Publications style
Shi X, Ye L, Xu S, Guo G, Zuo Z, Ye M, Zhu L, Li B, Xue X, Lin Q, Lin Q, et al: Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus. Mol Med Rep 22: 841-849, 2020.
APA
Shi, X., Ye, L., Xu, S., Guo, G., Zuo, Z., Ye, M. ... Ding, X. (2020). Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus. Molecular Medicine Reports, 22, 841-849. https://doi.org/10.3892/mmr.2020.11166
MLA
Shi, X., Ye, L., Xu, S., Guo, G., Zuo, Z., Ye, M., Zhu, L., Li, B., Xue, X., Lin, Q., Ding, X."Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus". Molecular Medicine Reports 22.2 (2020): 841-849.
Chicago
Shi, X., Ye, L., Xu, S., Guo, G., Zuo, Z., Ye, M., Zhu, L., Li, B., Xue, X., Lin, Q., Ding, X."Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus". Molecular Medicine Reports 22, no. 2 (2020): 841-849. https://doi.org/10.3892/mmr.2020.11166
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