Open Access

miR‑125b‑mediated regulation of cell proliferation through the Jagged‑1/Notch signaling pathway by inhibiting BRD4 expression in psoriasis

  • Authors:
    • Min Pan
    • Yao Huang
    • Xiaofang Zhu
    • Xiangfei Lin
    • Dan Luo
  • View Affiliations

  • Published online on: April 24, 2019     https://doi.org/10.3892/mmr.2019.10187
  • Pages: 5227-5236
  • Copyright: © Pan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Psoriasis is a chronic inflammatory disease characterized by the abnormal differentiation and hyperproliferation of epidermal keratinocytes. The aim of the present study was to investigate the mechanism by which microRNA‑125b (miR‑125b) inhibits the activation of the bromodomain‑containing protein 4 (BRD4)/Notch signaling pathway in psoriasis. The contents of associated miRNAs in serum samples from 32 patients with psoriasis were detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The most significantly downregulated miRNA, miR‑125b, was screened out. In experiments using HaCaT cells, the association between miR‑125b and cell proliferation was observed using a Cell Counting Kit‑8 assay, that between miR‑125b and the Notch signaling pathway was observed by western blotting and RT‑qPCR, and that between miR‑125b and the upstream molecule BRD4 of the Notch signaling pathway was observed by luciferase reporter assay and western blotting. The proliferation of HaCaT cells became apparent following miR‑125b inhibition. The Jagged‑1 ligand in the Notch signaling pathway was upregulated, the active intracellular domain of the Notch1 receptor was increasingly truncated, and the Notch signaling pathway was activated. Furthermore, the inhibited miR‑125b contributed directly toward the upstream protein BRD4 3'‑UTR of Jagged‑1, ultimately activating the Notch signaling pathway with the upregulation of Jagged‑1. In conclusion, the proliferation of HaCaT cells mediated by the Jagged‑1/Notch signaling pathway was decreased with the miR‑125b‑mediated inhibition of BRD4 expression. Therefore, miR‑125b may be a biomarker and potential therapeutic target for psoriasis treatment.

References

1 

Smith RL, Warren RB, Griffiths CE and Worthington J: Genetic susceptibility to psoriasis: An emerging picture. Genome Med. 1:722009. View Article : Google Scholar : PubMed/NCBI

2 

Nestle FO, Kaplan DH and Barker J: Psoriasis. N Engl J Med. 361:496–509. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Lowes MA, Bowcock AM and Krueger JG: Pathogenesis and therapy of psoriasis. Nature. 445:866–873. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Miele L: Notch signaling. Clin Cancer Res. 12:1074–1079. 2006. View Article : Google Scholar : PubMed/NCBI

5 

Jiao Z, Wang W, Guo M, Zhang T, Chen L, Wang Y, You H and Li J: Expression analysis of Notch-related molecules in peripheral blood T helper cells of patients with rheumatoid arthritis. Scand J Rheumatol. 39:26–32. 2010. View Article : Google Scholar : PubMed/NCBI

6 

Murea M, Park JK, Sharma S, Kato H, Gruenwald A, Niranjan T, Si H, Thomas DB, Pullman JM, Melamed ML and Susztak K: Expression of Notch pathway proteins correlates with albuminuria, glomerulosclerosis, and renal function. Kidney Int. 78:514–522. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Nickoloff BJ and Nestle FO: Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest. 113:1664–1675. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Lehar SM and Bevan MJ: Immunology: Polarizing a T-cell response. Nature. 430:150–151. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Napolitani G, Rinaldi A, Bertoni F, Sallusto F and Lanzavecchia A: Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol. 6:769–776. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Xia J and Zhang W: MicroRNAs in normal and psoriatic skin. Physiol Genomics. 46:113–122. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Yan S, Xu Z, Lou F, Zhang L, Ke F, Bai J, Liu Z, Liu J, Wang H, Zhu H, et al: NF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis. Nat Commun. 6:76522015. View Article : Google Scholar : PubMed/NCBI

12 

Meisgen F, Xu N, Wei T, Janson PC, Obad S, Broom O, Nagy N, Kauppinen S, Kemény L, Ståhle M, et al: MiR-21 is up-regulated in psoriasis and suppresses T cell apoptosis. Exp Dermatol. 21:312–314. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Zhang L, Stokes N, Polak L and Fuchs E: Specific microRNAs are preferentially expressed by skin stem cells to balance self-renewal and early lineage commitment. Cell Stem Cell. 8:294–308. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Xu N, Brodin P, Wei T, Meisgen F, Eidsmo L, Nagy N, Kemeny L, Ståhle M, Sonkoly E and Pivarcsi A: MiR-125b, a microRNA downregulated in psoriasis, modulates keratinocyte proliferation by targeting FGFR2. J Invest Dermatol. 131:1521–1529. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Huang RY, Li L, Wang MJ, Chen XM, Huang QC and Lu CJ: An exploration of the role of MicroRNAs in psoriasis: A systematic review of the literature. Medicine (Baltimore). 94:e20302015. View Article : Google Scholar : PubMed/NCBI

16 

Andrieu GP, Shafran JS, Deeney JT, Bharadwaj KR, Rangarajan A and Denis GV: BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment. J Leukoc Biol. 104:265–274. 2018. View Article : Google Scholar : PubMed/NCBI

17 

Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J, et al: Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem. 287:28840–28851. 2012. View Article : Google Scholar : PubMed/NCBI

18 

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

19 

Crow JM: Therapeutics: Silencing psoriasis. Nature. 492:S58–S59. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Ota T, Takekoshi S, Takagi T, Kitatani K, Toriumi K, Kojima T, Kato M, Ikoma N, Mabuchi T and Ozawa A: Notch signaling may be involved in the abnormal differentiation of epidermal keratinocytes in psoriasis. Acta Histochem Cytochem. 47:175–183. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Jinnin M: Recent progress in studies of miRNA and skin diseases. J Dermatol. 42:551–558. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Liu Q, Wu DH, Han L, Deng JW, Zhou L, He R, Lu CJ and Mi QS: Roles of microRNAs in psoriasis: Immunological functions and potential biomarkers. Exp Dermatol. 26:359–367. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Wei T, Folkersen L, Biskup E, Xu N, Manfe V, Niazi O and Gniadecki R: Ubiquitin-specific peptidase 2 as a potential link between microRNA-125b and psoriasis. Br J Dermatol. 176:723–731. 2017. View Article : Google Scholar : PubMed/NCBI

24 

Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, Fabbri M, Alder H, Liu CG, Calin GA and Croce CM: Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol. 179:5082–5089. 2007. View Article : Google Scholar : PubMed/NCBI

25 

Boukamp P, Petrussevska RT, Breitkreutz D, Hornung J, Markham A and Fusenig NE: Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 106:761–771. 1988. View Article : Google Scholar : PubMed/NCBI

26 

Schürer N, Köhne A, Schliep V, Barlag K and Goerz G: Lipid composition and synthesis of HaCaT cells, an immortalized human keratinocyte line, in comparison with normal human adult keratinocytes. Exp Dermatol. 2:179–185. 1993. View Article : Google Scholar : PubMed/NCBI

27 

Thélu J, Rossio P and Favier B: Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing. BMC Dermatol. 2:72002. View Article : Google Scholar : PubMed/NCBI

28 

Abdou AG, Maraee AH, Sharaf A and Elnaidany NF: Up-regulation of Notch-1 in psoriasis: An immunohistochemical study. Ann Diagn Pathol. 16:177–184. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Rooney P, Connolly M, Gao W, McCormick J, Biniecka M, Sullivan O, Kirby B, Sweeney C, Molloy E, Markham T, et al: Notch-1 mediates endothelial cell activation and invasion in psoriasis. Exp Dermatol. 23:113–118. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Skarmoutsou E, Trovato C, Granata M, Rossi GA, Mosca A, Longo V, Gangemi P, Pettinato M, D'Amico F and Mazzarino MC: Biological therapy induces expression changes in Notch pathway in psoriasis. Arch Dermatol Res. 307:863–873. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Kovall RA, Gebelein B, Sprinzak D and Kopan R: The canonical Notch signaling pathway: Structural and biochemical insights into shape, sugar, and force. Dev Cell. 41:228–241. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Bray SJ and Gomez-Lamarca M: Notch after cleavage. Curr Opin Cell Biol. 51:103–109. 2018. View Article : Google Scholar : PubMed/NCBI

33 

Locatelli M and Curigliano G: Notch inhibitors and their role in the treatment of triple negative breast cancer: Promises and failures. Curr Opin Oncol. 29:411–427. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Andrieu G, Tran AH, Strissel KJ and Denis GV: BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling. Cancer Res. 76:6555–6567. 2016. View Article : Google Scholar : PubMed/NCBI

35 

Diani M, Altomare G and Reali E: T cell responses in psoriasis and psoriatic arthritis. Autoimmun Rev. 14:286–292. 2015. View Article : Google Scholar : PubMed/NCBI

36 

Chen H, Liu H, Lu C, Wang M, Li X, Zhao H, Yan Y, Yu W, Han L and Dai Z: PSORI-CM02 formula increases CD4+ Foxp3+ regulatory T cell frequency and ameliorates imiquimod-induced psoriasis in mice. Front Immunol. 8:17672018. View Article : Google Scholar : PubMed/NCBI

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June 2019
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Copy and paste a formatted citation
APA
Pan, M., Huang, Y., Zhu, X., Lin, X., & Luo, D. (2019). miR‑125b‑mediated regulation of cell proliferation through the Jagged‑1/Notch signaling pathway by inhibiting BRD4 expression in psoriasis. Molecular Medicine Reports, 19, 5227-5236. https://doi.org/10.3892/mmr.2019.10187
MLA
Pan, M., Huang, Y., Zhu, X., Lin, X., Luo, D."miR‑125b‑mediated regulation of cell proliferation through the Jagged‑1/Notch signaling pathway by inhibiting BRD4 expression in psoriasis". Molecular Medicine Reports 19.6 (2019): 5227-5236.
Chicago
Pan, M., Huang, Y., Zhu, X., Lin, X., Luo, D."miR‑125b‑mediated regulation of cell proliferation through the Jagged‑1/Notch signaling pathway by inhibiting BRD4 expression in psoriasis". Molecular Medicine Reports 19, no. 6 (2019): 5227-5236. https://doi.org/10.3892/mmr.2019.10187