Role of the long non‑coding RNA HOTAIR/miR‑126 axis in an <em>in vitro</em> psoriasis model

Zha,Weifeng; Guo,Bo; Chen,Shuyue; Lu,Junwei; Shan,Yunyun

doi:10.3892/etm.2021.9878

Role of the long non‑coding RNA HOTAIR/miR‑126 axis in an in vitro psoriasis model

Authors:
- Weifeng Zha
- Bo Guo
- Shuyue Chen
- Junwei Lu
- Yunyun Shan
View Affiliations

Affiliations: Department of Dermatology, Third People's Hospital of Hangzhou, Hangzhou, Zhejiang 310009, P.R. China, Department of Dermatology, Tongxiang Dermatosis Prevention Institute, Tongxiang, Zhejiang 314500, P.R. China, Department of Acupuncture, Integrated Chinese and Western Medicine Hospital of Xihu, Hangzhou, Zhejiang 310030, P.R. China
Published online on: March 1, 2021 https://doi.org/10.3892/etm.2021.9878
Article Number: 450
Copyright: © Zha et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Psoriasis is a T‑cell‑mediated inflammatory skin disease that is characterized by excessive keratinocyte proliferation and persistent skin inflammation. Accumulating evidence suggests that long non‑coding RNAs (lncRNAs) are dysregulated in a number of inflammatory conditions. In the present study, an in vitro psoriasis cell model was established. Human HaCaT keratinocytes were activated using the inflammatory factor IL‑22. Briefly, HaCaT cells were starved in serum‑free DMEM for 24 h and then stimulated with 100 ng/ml IL‑22 in serum‑free DMEM for 24 h. Previous research indicated that HOX transcript antisense RNA (HOTAIR) may participate in the development of psoriasis. First, reverse transcription‑quantitative PCR (RT‑qPCR) analysis was performed to detect HOTAIR expression. The results indicated that HOTAIR expression was reduced in IL‑22‑stimulated HaCaT cells. Subsequently, a dual‑luciferase reporter assay was performed to verify the binding site between HOTAIR and microRNA (miR)‑126. The RT‑qPCR results indicated that miR‑126 expression was increased in IL‑22‑stimulated HaCaT cells. Moreover, the effects of HOTAIR and miR‑126 on IL‑22‑stimulated HaCaT cell proliferation and apoptosis were assessed. HaCaT cells were transfected with control‑plasmid, HOTAIR‑plasmid, HOTAIR‑plasmid + mimic control or HOTAIR‑plasmid + miR‑126 mimic for 24 h. At 24 h post‑transfection, the cells were stimulated with 100 ng/ml IL‑22 for 24 h and experiments were conducted. IL‑22 induced cell proliferation and suppressed apoptosis. However, HOTAIR‑plasmid inhibited cell viability and induced apoptosis in IL‑22‑stimulated HaCaT cells. In addition, the western blotting results indicated that HOTAIR‑plasmid increased cleaved caspase‑3 expression and the cleaved caspase‑3/caspase‑3 ratio, whereas the HOTAIR‑plasmid‑mediated effects were reversed by miR‑126 mimic. Collectively, the results of the present study demonstrated that the lncRNA‑HOTAIR/miR‑126 axis may be implicated in the regulation of psoriasis progression and may serve as a potential therapeutic target for psoriasis.

View Figures

View References

1	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.PubMed/NCBI View Article : Google Scholar
2	Boehncke WH and Schön MP: Psoriasis. Lancet. 386:983–994. 2015.PubMed/NCBI View Article : Google Scholar
3	Parisi R, Symmons DP, Griffiths CE and Ashcroft DM: Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of psoriasis: A systematic review of incidence and prevalence. J Invest Dermatol. 133:377–385. 2013.PubMed/NCBI View Article : Google Scholar
4	Ritchlin CT, Colbert RA and Gladman DD: Psoriatic arthritis. N Engl J Med. 376:957–970. 2017.PubMed/NCBI View Article : Google Scholar
5	Liakou AI and Zouboulis CC: Links and risks associated with psoriasis and metabolic syndrome. Psoriasis (Auckl). 5:125–128. 2015.PubMed/NCBI View Article : Google Scholar
6	Vide J and Magina S: Moderate to severe psoriasis treatment challenges through the era of biological drugs. An Bras Dermatol. 92:668–674. 2017.PubMed/NCBI View Article : Google Scholar
7	Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, et al: The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: A systematic review and meta-analysis. Ann Rheum Dis. 74:480–489. 2015.PubMed/NCBI View Article : Google Scholar
8	Geller S, Xu H, Lebwohl M, Nardone B, Lacouture ME and Kheterpal M: Malignancy risk and recurrence with psoriasis and its treatments: A concise update. Am J Clin Dermatol. 19:363–375. 2018.PubMed/NCBI View Article : Google Scholar
9	Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC and Morel F: IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol. 174:3695–3702. 2005.PubMed/NCBI View Article : Google Scholar
10	Wolk K, Witte E, Wallace E, Döcke WD, Kunz S, Asadullah K, Volk HD, Sterry W and Sabat R: IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: A potential role in psoriasis. Eur J Immunol. 36:1309–1323. 2006.PubMed/NCBI View Article : Google Scholar
11	Amaral PP, Dinger ME, Mercer TR and Mattick JS: The eukaryotic genome as an RNA machine. Science. 319:1787–1789. 2008.PubMed/NCBI View Article : Google Scholar
12	Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, Huarte M, Zuk O, Carey BW, Cassady JP, et al: Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 458:223–227. 2009.PubMed/NCBI View Article : Google Scholar
13	Nagano T and Fraser P: No-nonsense functions for long noncoding RNAs. Cell. 145:178–181. 2011.PubMed/NCBI View Article : Google Scholar
14	Lekka E and Hall J: Noncoding RNAs in disease. FEBS Lett. 592:2884–2900. 2018.PubMed/NCBI View Article : Google Scholar
15	Kopp F and Mendell JT: Functional classification and experimental dissection of long noncoding RNAs. Cell. 172:393–407. 2018.PubMed/NCBI View Article : Google Scholar
16	Wang KC and Chang HY: Molecular mechanisms of long noncoding RNAs. Mol Cell. 43:904–914. 2011.PubMed/NCBI View Article : Google Scholar
17	Liu Y, Ferguson JF, Xue C, Ballantyne RL, Silverman IM, Gosai SJ, Serfecz J, Morley MP, Gregory BD, Li M, et al: Tissue-specific RNA-Seq in human evoked inflammation identifies blood and adipose LincRNA signatures of cardiometabolic diseases. Arterioscler Thromb Vasc Biol. 34:902–912. 2014.PubMed/NCBI View Article : Google Scholar
18	Liu YW, Sun M, Xia R, Zhang EB, Liu XH, Zhang ZH, Xu TP, De W, Liu BR and Wang ZX: LincHOTAIR epigenetically silences miR34a by binding to PRC2 to promote the epithelial-to-mesenchymal transition in human gastric cancer. Cell Death Dis. 6(e1802)2015.PubMed/NCBI View Article : Google Scholar
19	Chang S, Chen B, Wang X, Wu K and Sun Y: Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression. BMC Cancer. 17(248)2017.PubMed/NCBI View Article : Google Scholar
20	Lu W, Zhang H, Niu Y, Wu Y, Sun W, Li H, Kong J, Ding K, Shen HM, Wu H, et al: Long non-coding RNA linc00673 regulated non-small cell lung cancer proliferation, migration, invasion and epithelial mesenchymal transition by sponging miR-150-5p. Mol Cancer. 16(118)2017.PubMed/NCBI View Article : Google Scholar
21	Zheng J, Huang X, Tan W, Yu D, Du Z, Chang J, Wei L, Han Y, Wang C, Che X, et al: Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. Nat Genet. 48:747–757. 2016.PubMed/NCBI View Article : Google Scholar
22	Sha M, Lin M, Wang J, Ye J, Xu J, Xu N and Huang J: Long non-coding RNA MIAT promotes gastric cancer growth and metastasis through regulation of miR-141/DDX5 pathway. J Exp Clin Cancer Res. 37(58)2018.PubMed/NCBI View Article : Google Scholar
23	Lu Z, Li Y, Wang J, Che Y, Sun S, Huang J, Chen Z and He J: Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway. J Exp Clin Cancer Res. 36(54)2017.PubMed/NCBI View Article : Google Scholar
24	Yan J, Song J, Qiao M, Zhao X, Li R, Jiao J and Sun Q: Long noncoding RNA expression profile and functional analysis in psoriasis. Mol Med Rep. 19:3421–3430. 2019.PubMed/NCBI View Article : Google Scholar
25	Ahn R, Gupta R, Lai K, Chopra N, Arron ST and Liao W: Network analysis of psoriasis reveals biological pathways and roles for coding and long non-coding RNAs. BMC Genomics. 17(841)2016.PubMed/NCBI View Article : Google Scholar
26	Jia HY, Zhang K, Lu WJ, Xu GW, Zhang JF and Tang ZL: lncRNA MEG3 influences the proliferation and apoptosis of psoriasis epidermal cells by targeting miR-21/caspase-8. BMC Mol Cell Biol. 20(46)2019.PubMed/NCBI View Article : Google Scholar
27	Gao J, Chen F, Hua M, Guo J, Nong Y, Tang Q, Zhong F and Qin L: Knockdown of lncRNA MIR31HG inhibits cell proliferation in human HaCaT keratinocytes. Biol Res. 51(30)2018.PubMed/NCBI View Article : Google Scholar
28	Qiao M, Li R, Zhao X, Yan J and Sun Q: Up-regulated lncRNA-MSX2P1 promotes the growth of IL-22-stimulated keratinocytes by inhibiting miR-6731-5p and activating S100A7. Exp Cell Res. 363:243–254. 2018.PubMed/NCBI View Article : Google Scholar
29	Széll M, Danis J, Bata-Csörgő Z and Kemény L: PRINS, a primate-specific long non-coding RNA, plays a role in the keratinocyte stress response and psoriasis pathogenesis. Pflugers Arch. 468:935–943. 2016.PubMed/NCBI View Article : Google Scholar
30	Tang Q and Hann SS: HOTAIR: An oncogenic long non-coding RNA in human cancer. Cell Physiol Biochem. 47:893–913. 2018.PubMed/NCBI View Article : Google Scholar
31	Yang T, He X, Chen A, Tan K and Du X: lncRNA HOTAIR contributes to the malignancy of hepatocellular carcinoma by enhancing epithelial-mesenchymal transition via sponging miR-23b-3p from ZEB1. Gene. 670:114–122. 2018.PubMed/NCBI View Article : Google Scholar
32	Rakhshan A, Zarrinpour N, Moradi A, Ahadi M, Omrani MD, Ghafouri-Fard S and Taheri M: A single nucleotide polymorphism within HOX Transcript Antisense RNA (HOTAIR) is associated with risk of psoriasis. Int J Immunogenet. 47:430–434. 2020.PubMed/NCBI View Article : Google Scholar
33	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.PubMed/NCBI View Article : Google Scholar
34	Xu L and Leng H, Shi X, Ji J, Fu J and Leng H: miR-155 promotes cell proliferation and inhibits apoptosis by PTEN signaling pathway in the psoriasis. Biomed Pharmacother. 90:524–530. 2017.PubMed/NCBI View Article : Google Scholar
35	Cheung L, Fisher RM, Kuzmina N, Li D, Li X, Werngren O, Blomqvist L, Ståhle M and Landén NX: Psoriasis skin inflammation-induced microRNA-26b targets NCEH1 in underlying subcutaneous adipose tissue. J Invest Dermatol. 136:640–648. 2016.PubMed/NCBI View Article : Google Scholar
36	Yan J, Dang Y, Liu S, Zhang Y and Zhang G: lncRNA HOTAIR promotes cisplatin resistance in gastric cancer by targeting miR-126 to activate the PI3K/AKT/MRP1 genes. Tumour Biol. 37(30)2016.PubMed/NCBI View Article : Google Scholar
37	Jiang B, Tang Y, Wang H, Chen C, Yu W, Sun H, Duan M, Lin X and Liang P: Down-regulation of long non-coding RNA HOTAIR promotes angiogenesis via regulating miR-126/SCEL pathways in burn wound healing. Cell Death Dis. 11(61)2020.PubMed/NCBI View Article : Google Scholar
38	Wang R, Wang FF, Cao HW and Yang JY: miR-223 regulates proliferation and apoptosis of IL-22-stimulated HaCat human keratinocyte cell lines via the PTEN/Akt pathway. Life Sci. 230:28–34. 2019.PubMed/NCBI View Article : Google Scholar
39	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)) Method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
40	Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, et al: Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 129:1311–1323. 2007.PubMed/NCBI View Article : Google Scholar
41	Zhang C, Xu L, Deng G, Ding Y, Bi K, Jin H, Shu J, Yang J, Deng H, Wang Z, et al: Exosomal HOTAIR promotes proliferation, migration and invasion of lung cancer by sponging miR-203. Sci China Life Sci. 63:1265–1268. 2020.PubMed/NCBI View Article : Google Scholar
42	Liu XH, Sun M, Nie FQ, Ge YB, Zhang EB, Yin DD, Kong R, Xia R, Lu KH, Li JH, et al: lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol Cancer. 13(92)2014.PubMed/NCBI View Article : Google Scholar
43	Gao JZ, Li J, Du JL and Li XL: Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence. Oncol Lett. 11:1791–1798. 2016.PubMed/NCBI View Article : Google Scholar
44	Lowes MA, Suárez-Fariñas M and Krueger JG: Immunology of psoriasis. Annu Rev Immunol. 32:227–255. 2014.PubMed/NCBI View Article : Google Scholar
45	Jadali Z and Eslami MB: T cell immune responses in psoriasis. Iran J Allergy Asthma Immunol. 13:220–230. 2014.PubMed/NCBI
46	Soltanzadeh-Yamchi M, Shahbazi M, Aslani S and Mohammadnia-Afrouzi M: MicroRNA signature of regulatory T cells in health and autoimmunity. Biomed Pharmacother. 100:316–323. 2018.PubMed/NCBI View Article : Google Scholar
47	Qu Y, Wu J, Deng JX, Zhang YP, Liang WY, Jiang ZL, Yu QH and Li J: MicroRNA-126 affects rheumatoid arthritis synovial fibroblast proliferation and apoptosis by targeting PIK3R2 and regulating PI3K-AKT signal pathway. Oncotarget. 7:74217–74226. 2016.PubMed/NCBI View Article : Google Scholar
48	Liang Y, Zhao S, Liang G, Zhao M and Lu Q: DNA methylation status of miR-126 and its host gene EGFL7 in CD4⁺ T cells from patients with systemic lupus erythematosus. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 38:793–797. 2013.PubMed/NCBI View Article : Google Scholar : (In Chinese).
49	Thorlacius-Ussing G, Schnack Nielsen B, Andersen V, Holmstrøm K and Pedersen AE: Expression and localization of miR-21 and miR-126 in mucosal tissue from patients with inflammatory bowel disease. Inflamm Bowel Dis. 23:739–752. 2017.PubMed/NCBI View Article : Google Scholar
50	Feng SK, Wang L, Liu W, Zhong Y and Xu SJ: miR-126 correlates with increased disease severity and promotes keratinocytes proliferation and inflammation while suppresses cells' apoptosis in psoriasis. J Clin Lab Anal. 32(e22588)2018.PubMed/NCBI View Article : Google Scholar