https://doi.org/10.4081/ejh.2022.3275
MicroRNA-17-3p is upregulated in psoriasis and regulates keratinocyte hyperproliferation and pro-inflammatory cytokine secretion by targeting CTR9
Submitted: 18 May 2021
Accepted: 31 December 2021
Published: 12 January 2022
Accepted: 31 December 2021
Abstract Views: 1408
PDF: 591
Supplementary: 109
HTML: 25
Supplementary: 109
HTML: 25
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Psoriasis is a chronic inflammatory skin disease. Although miRNAs are reported to be associated with the pathogenesis of psoriasis, the contribution of individual microRNAs toward psoriasis remains unclear. The miR-17-92 cluster regulates cell growth and immune functions that are associated with psoriasis. miR-17-3p is a member of miR-17-92 cluster; however, its role in dermatological diseases remains unclear. Our study aims at investigating the effects of miR-17-3p and its potential target gene on keratinocytes proliferation and secretion of pro-inflammatory cytokine and their involvement in psoriasis. Initially, we found that miR-17-3p was upregulated in psoriatic skin lesions, and bioinformatic analyses suggested that CTR9 is likely to be a target gene of miR-17-3p. Quantitative reverse-transcriptase PCR and immunohistochemical analysis revealed that CTR9 expression was downregulated in psoriatic lesions. Using dual-luciferase reporter assays, we identified CTR9 as a direct target of miR-17-3p. Further functional experiments demonstrated that miR-17-3p promoted the proliferation and pro-inflammatory cytokine secretion of keratinocytes, whereas CTR9 exerted the opposite effects. Gain-of-function studies confirmed that CTR9 suppression partially accounted for the effects of miR-17-3p in keratinocytes. Furthermore, Western blot revealed that miR-17-3p activates the downstream STAT3 signaling pathway while CTR9 inactivates the STAT3 signaling pathway. Together, these findings indicate that miR-17-3p regulates keratinocyte proliferation and pro-inflammatory cytokine secretion partially by targeting the CTR9, which inactivates the downstream STAT3 protein, implying that miR-17-3p might be a novel therapeutic target for psoriasis.
Boehncke WH, Schön MP. Psoriasis. Lancet 2015;386:983-94.
DOI: https://doi.org/10.1016/S0140-6736(14)61909-7
Albanesi C, Madonna S, Gisondi P, Girolomoni G. The interplay between keratinocytes and immune cells in the pathogenesis of psoriasis. Front Immunol 2018;9:1549.
DOI: https://doi.org/10.3389/fimmu.2018.01549
Raju SS. Psoriasis and lasting implications. Expert Rev Clin Immunol 2014;10:175-7.
DOI: https://doi.org/10.1586/1744666X.2014.872033
Liang XQ, Ou CX, Zhuang JY, Li JS, Zhang FF, Zhong YQ, et al. Interplay between skin microbiota dysbiosis and the host immune system in psoriasis: Potential pathogenesis. Front Immunol 2021;12:764384.
DOI: https://doi.org/10.3389/fimmu.2021.764384
Di Fusco D, Stolfi C, Di Grazia A. Albendazole negatively regulates keratinocyte proliferation. Clin Sci 2020;134:907-20.
DOI: https://doi.org/10.1042/CS20191215
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215-33.
DOI: https://doi.org/10.1016/j.cell.2009.01.002
Hawkes JE, Nguyen GH, Fujita M, Florell SR, Callis Duffin K, Krueger GG, et al. microRNAs in Psoriasis. J. Invest. Dermatol 2016;136:365-71.
DOI: https://doi.org/10.1038/JID.2015.409
Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease. Cell Death Differ 2013;20:1603-14.
DOI: https://doi.org/10.1038/cdd.2013.125
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature 2005;435:828-33.
DOI: https://doi.org/10.1038/nature03552
Kuo G, Wu CY , Yang HY. MiR-17-92 cluster and immunity. J Formos Med Assoc 2019;18:2-6.
DOI: https://doi.org/10.1016/j.jfma.2018.04.013
Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic MicroRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res 2005;65:9628-32.
DOI: https://doi.org/10.1158/0008-5472.CAN-05-2352
Yuan J, Su Z, Gu W, Shen X, Zhao Q, Shi L, et al. MiR-19b and miR-20a suppress apoptosis, promote proliferation and induce tumorigenicity of multiple myeloma cells by targeting PTEN. Cancer Biomark 2019;24:279-89.
DOI: https://doi.org/10.3233/CBM-182182
Wang W, Zhang A, Hao Y, Wang G, Jia Z. The emerging role of miR-19 in glioma. J Cell Mol Med 2018;22:4611-6.
DOI: https://doi.org/10.1111/jcmm.13788
Xiang P, Yeung YT, Wang JH, Wu Q, Du RJ, Huang CT, et al. miR-17-3p promotes the proliferation of multiple myeloma cells by downregulating P21 expression through LMLN inhibition. Int J Cancer 2021;148:3071-85.
DOI: https://doi.org/10.1002/ijc.33528
Wu S, Chen H, Han N, Zhang CX, Yan HT. Long noncoding RNA PVT1 silencing prevents the development of uveal melanoma by impairing microRNA-17-3p-dependent MDM2 upregulation. Invest Ophthalmol Vis Sci 2019;60:4904-14.
DOI: https://doi.org/10.1167/iovs.19-27704
Suzuki H, Miyazono K. Emerging complexity of microRNA generation cascades. J Biochem 2011;149:15-25.
DOI: https://doi.org/10.1093/jb/mvq113
Marsh DJ, Ma Y, Dickson KA. Histone monoubiquitination in chromatin remodelling: Focus on the Histone H2B interactome and cancer. Cancers 2020;12:3462.
DOI: https://doi.org/10.3390/cancers12113462
Youn MY, Yoo HS, Kim MJ, Hwang SY, Choi Y, Desiderio SV, et al. hCTR9, a component of Paf1 complex, participates in the transcription of interleukin 6-responsive genes through regulation of STAT3-DNA interactions. J Biol Chem 2007;282:34727-34.
DOI: https://doi.org/10.1074/jbc.M705411200
Qiao P, Guo W, Ke Y, Fang H, Zhuang Y, Jiang M, et al. Mechanical stretch exacerbates psoriasis by stimulating keratinocyte proliferation and cytokine production. J Invest Dermatol 2019;139 :1470-9.
DOI: https://doi.org/10.1016/j.jid.2018.12.019
Sileno S, Beji S, D'Agostino M, Carassiti A, Melillo G, Magenta A. microRNAs involved in psoriasis and cardiovascular diseases. Vasc Biol 2021;3:R49-R68.
DOI: https://doi.org/10.1530/VB-21-0007
Xiuli Y, Honglin W. miRNAs flowing up and down: The concerto of psorisis. Front Med (Lausanne) 2021;8:646796.
DOI: https://doi.org/10.3389/fmed.2021.646796
Zhang W, Yi X, An Y, Guo S, Li S, Song P, et al. MicroRNA-17-92 cluster promotes the proliferation and the chemokine production of keratinocytes: implication for the pathogenesis of psoriasis. Cell Death Dis 2018;9:567.
DOI: https://doi.org/10.1038/s41419-018-0621-y
Alatas ET, Kara M, Dogan G, Belli AA. Blood microRNA expressions in patients with mild to moderate psoriasis and the relationship between microRNAs and psoriasis activity. An Bras Dermatol 2020;95:702-7.
DOI: https://doi.org/10.1016/j.abd.2020.07.001
Takakura S, Mitsutake N, Nakashima M, Namba H, Saenko VA, Rogounovitch TI, et al. Oncogenic role of miR-17-92 cluster in anaplastic thyroid cancer cells. Cancer Sci 2008;99:1147-54.
DOI: https://doi.org/10.1111/j.1349-7006.2008.00800.x
Lu D, Tang L, Zhuang Y, Zhao P. miR-17-3P regulates the proliferation and survival of colon cancer cells by targeting Par4. Mol Med Rep 2018;17:618-23.
DOI: https://doi.org/10.3892/mmr.2017.7863
Shan SW, Fang L, Shatseva T, Rutnam ZJ, Yang X, Du W, et al. Mature miR-17-5p and passenger miR-17-3p induce hepatocellular carcinoma by targeting PTEN, GalNT7 and vimentin in different signal pathways. J Cell Sci 2013;126:1517.
DOI: https://doi.org/10.1242/jcs.122895
Li H, Yang BB. Stress response of glioblastoma cells mediated by miR-17-5p targeting PTEN and the passenger strand miR-17-3p targeting MDM2. Oncotarget 2012;3:1653-68.
DOI: https://doi.org/10.18632/oncotarget.810
Yan H, Song K, Zhang G. MicroRNA-17-3p promotes keratinocyte cells growth and metastasis via targeting MYOT and regulating Notch1/NF-kappaB pathways. Pharmazie 2017;72:543-9.
Hanks S, Perdeaux ER, Seal S,Ruark E, Mahamdallie SS, Murray A, et al. Germline mutations in the PAF1 complex gene CTR9 predispose to Wilms tumour. Nat Commun 2014;5:4398.
DOI: https://doi.org/10.1038/ncomms5398
Zeng H, Xu W. Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis. Genes Dev 2015;29:2153-67.
DOI: https://doi.org/10.1101/gad.268722.115
Yoo HS, Choi Y, Ahn N, Lee S, Kim WU, Jang MS, et al. Transcriptional regulator CTR9 inhibits Th17 differentiation via repression of IL-17 expression. J Immunol 2014;192:1440-8.
DOI: https://doi.org/10.4049/jimmunol.1201952
Lee H, Lee JW, Yoo KD, Yoo JY, Lee JP, Kim DK, et al. Cln 3-requiring 9 is a negative regulator of Th17 pathway-driven inflammation in anti-glomerular basement membrane glomerulonephritis. Am J Physiol Renal Physiol 2016;311:F505-19.
DOI: https://doi.org/10.1152/ajprenal.00533.2015
Li B, Huang L, Lv P, Li X, Liu G, Chen Y, et al. The role of Th17 cells in psoriasis. Immunol Res 2020;68:296-309.
DOI: https://doi.org/10.1007/s12026-020-09149-1
Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med 2005;11:43-9.
DOI: https://doi.org/10.1038/nm1162
Schüttler D, Clauss S, Weckbach LT, Brunner S. Molecular mechanisms of cardiac remodeling and regeneration in physical exercise. Cells 2019;8:1128.
DOI: https://doi.org/10.3390/cells8101128
Nosbaum A, Dahel K, Goujon C, Nicolas JF, Mengeaud V, Vocanson M. Psoriasis is a disease of the entire skin: non-lesional skin displays a prepsoriasis phenotype. Eur J Dermatol 2021;31:143-54.
DOI: https://doi.org/10.1684/ejd.2021.4015
How to Cite
Li, Q., Zhang, J., Liu, S., Zhang, F., Zhuang, J., & Chen, Y. (2022). MicroRNA-17-3p is upregulated in psoriasis and regulates keratinocyte hyperproliferation and pro-inflammatory cytokine secretion by targeting <em>CTR9</em>. European Journal of Histochemistry, 66(1). https://doi.org/10.4081/ejh.2022.3275
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- H. Huang, W. Wang, P. Liu, Y. Jiang, Y. Zhao, H. Wei, W. Niu, TRPC1 expression and distribution in rat hearts , European Journal of Histochemistry: Vol. 53 No. 4 (2009)
- RH Ponce, CS Carriazo, NT Vermouth, Lactate dehydrogenase activity of rat epididymis and spermatozoa: Effect of constant light , European Journal of Histochemistry: Vol. 45 No. 2 (2001)
- A Mandich, A Massari, S Bottero, G Marino, Histological and histochemical study of female germ cell development in the dusky grouper Epinephelus marginatus (Lowe, 1834) , European Journal of Histochemistry: Vol. 46 No. 1 (2002)
- Manuela Malatesta, Histological and Histochemical Methods - Theory and practice , European Journal of Histochemistry: Vol. 60 No. 1 (2016)
- S Passinen, T Ylikomi, Evidence for the existence of an oligomeric, non-DNA-binding complex of the progesterone receptor in the cytoplasm , European Journal of Histochemistry: Vol. 47 No. 3 (2003)
- T Cremer, C Cremer, Rise, fall and resurrection of chromosome territories: a historical perspective. Part I. The rise of chromosome territories , European Journal of Histochemistry: Vol. 50 No. 3 (2006)
- RG Steinbeck, Pathologic mitoses and pathology of mitosis in tumorigenesis , European Journal of Histochemistry: Vol. 45 No. 4 (2001)
- C Angelini, B Baccetti, P Piomboni, S Trombino, MG Aluigi, S Stringara, L Gallus, C Falugi, Acetylcholine synthesis and possible functions during sea urchin development , European Journal of Histochemistry: Vol. 48 No. 3 (2004)
You may also start an advanced similarity search for this article.
