LncRNA XIST promotes inflammation by downregulating GRα expression in the adenoids of children with OSAHS

Zhou,Zhen; Ni,Haifeng; Li,Yong; Jiang,Bo

doi:10.3892/etm.2021.9931

LncRNA XIST promotes inflammation by downregulating GRα expression in the adenoids of children with OSAHS

Authors:
- Zhen Zhou
- Haifeng Ni
- Yong Li
- Bo Jiang
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Affiliations: Department of Otolaryngology, Head and Neck Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China
Published online on: March 17, 2021 https://doi.org/10.3892/etm.2021.9931
Article Number: 500
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Whether glucocorticoid receptor α (GRα) serves a role in obstructive sleep apnea/hypopnea syndrome (OSAHS) remains unclear. However, it has been reported that GRα expression is decreased in the adenoids of patients with OSAHS. The present study aimed to evaluate the role of GRα in OSAHS and the underlying mechanism. Bioinformatics assays revealed that long noncoding RNA (lncRNA) X inactivate‑specific transcript (XIST) was closely associated with GRα. Furthermore, reverse transcription‑quantitative PCR showed that the expression of lncRNA XIST was significantly increased in the adenoids of patients with OSAHS compared with healthy controls. Further in vitro studies by Pearson correlation analysis, RNA pull‑down assay, western blot analysis and ELISA demonstrated that XIST significantly decreased the expression of GRα and that significantly increased the production of inflammatory cytokines, including interleukin (IL)‑8, tumor necrosis factor α, IL‑6 and IL‑1β, while the overexpression of GRα significantly decreased the production of these inflammatory cytokines in NP69 cells, a human nasopharyngeal epithelial cell line. Furthermore, XIST significantly increased the protein levels of nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) subunits, including Rel‑B, c‑Rel, P52, P50 and P65, which are associated with the transcription of cytokines. The stimulatory effect of XIST was significantly inhibited by the NF‑κB inhibitor EVP4593. These results indicated that the stimulatory effect of XIST was dependent on NF‑κB. In summary, the present study demonstrated that the XIST‑GRα‑NF‑κB signaling pathway contributed to inflammation in the adenoids of patients with OSAHS.

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1	Zhang L, Ou X, Zhu T and Lv X: Beneficial effects of estrogens in obstructive sleep apnea hypopnea syndrome. Sleep Breath. 24:7–13. 2020.PubMed/NCBI View Article : Google Scholar
2	Gonzaga C, Bertolami A, Bertolami M, Amodeo C and Calhoun D: Obstructive sleep apnea, hypertension and cardiovascular diseases. J Hum Hypertens. 29:705–12. 2015.PubMed/NCBI View Article : Google Scholar
3	Jordan AS and McEvoy RD: Gender differences in sleep apnea: Epidemiology, clinical presentation and pathogenic mechanisms. Sleep Med Rev. 7:377–389. 2003.PubMed/NCBI View Article : Google Scholar
4	Morong S, Hermsen B and de Vries N: Sleep-disordered breathing in pregnancy: A review of the physiology and potential role for positional therapy. Sleep Breath. 18:31–37. 2014.PubMed/NCBI View Article : Google Scholar
5	Snyder B and Cunningham RL: Sex differences in sleep apnea and comorbid neurodegenerative diseases. Steroids. 133:28–33. 2018.PubMed/NCBI View Article : Google Scholar
6	Evans RM: The steroid and thyroid hormone receptor superfamily. Science. 240:889–895. 1988.PubMed/NCBI View Article : Google Scholar
7	Ren R, Oakley RH, Cruz-Topete D and Cidlowski JA: Dual role for glucocorticoids in cardiomyocyte hypertrophy and apoptosis. Endocrinology. 153:5346–5360. 2012.PubMed/NCBI View Article : Google Scholar
8	Kim HK, Jeong YJ, Song IS, Noh YH, Seo KW, Kim M and Han J: Glucocorticoid receptor positively regulates transcription of FNDC5 in the liver. Sci Rep. 7(43296)2017.PubMed/NCBI View Article : Google Scholar
9	Kuo T, Chen TC, Yan S, Foo F, Ching C, McQueen A and Wang JC: Repression of glucocorticoid-stimulated angiopoietin-like 4 gene transcription by insulin. J Lipid Res. 55:919–28. 2014.PubMed/NCBI View Article : Google Scholar
10	Chen X and Li JR: Glucocorticoid receptor expression in the tonsils of children with obstructive sleep apnea hypopnea syndrome. Genet Mol Res. 15:2016.PubMed/NCBI View Article : Google Scholar
11	Choi SW, Kim HW and Nam JW: The small peptide world in long noncoding RNAs. Brief Bioinform. 20:1853–1864. 2019.PubMed/NCBI View Article : Google Scholar
12	Barth DA, Slaby O, Klec C, Juracek J, Drula R, Calin GA and Pichler M: Current concepts of non-coding RNAs in the pathogenesis of non-clear cell renal cell carcinoma. Cancers (Basel). 11(1580)2019.PubMed/NCBI View Article : Google Scholar
13	Rapicavoli NA, Qu K, Zhang J, Mikhail M, Laberge RM and Chang HY: A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. Elife. 2(e00762)2013.PubMed/NCBI View Article : Google Scholar
14	Carpenter S, Aiello D, Atianand MK, Ricci EP, Gandhi P, Hall LL, Byron M, Monks B, Henry-Bezy M, Lawrence JB, et al: A long noncoding RNA mediates both activation and repression of immune response genes. Science. 341:789–792. 2013.PubMed/NCBI View Article : Google Scholar
15	Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, Liao X, Iglehart JD, Livingston DM and Ganesan S: X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 9:121–132. 2006.PubMed/NCBI View Article : Google Scholar
16	McKiernan PJ, Molloy K, Cryan SA, McElvaney NG and Greene CM: Long noncoding RNA are aberrantly expressed in vivo in the cystic fibrosis bronchial epithelium. Int J Biochem Cell Biol. 52:184–191. 2014.PubMed/NCBI View Article : Google Scholar
17	Ma M, Pei Y, Wang X, Feng J, Zhang Y and Gao MQ: LncRNA XIST mediates bovine mammary epithelial cell inflammatory response via NF-kappaB/NLRP3 inflammasome pathway. Cell Prolif. 52(e12525)2019.PubMed/NCBI View Article : Google Scholar
18	Sadeghi A, Rostamirad A, Seyyedebrahimi S and Meshkani R: Curcumin ameliorates palmitate-induced inflammation in skeletal muscle cells by regulating JNK/NF-kB pathway and ROS production. Inflammopharmacology. 26:1265–1272. 2018.PubMed/NCBI View Article : Google Scholar
19	Nedjai B, Hitman GA, Church LD, Minden K, Whiteford ML, McKee S, Stjernberg S, Pettersson T, Ranki A, Hawkins PN, et al: Differential cytokine secretion results from p65 and c-Rel NF-κB subunit signaling in peripheral blood mononuclear cells of TNF receptor-associated periodic syndrome patients. Cell Immunol. 268:55–59. 2011.PubMed/NCBI View Article : Google Scholar
20	Ruland J: Return to homeostasis: Downregulation of NF-κB responses. Nature Immunol. 12:709–714. 2011.PubMed/NCBI View Article : Google Scholar
21	Lai JL, Liu YH, Liu C, Qi MP, Liu RN, Zhu XF, Zhou QG, Chen YY, Guo AZ and Hu CM: Indirubin inhibits LPS-induced inflammation via TLR4 abrogation mediated by the NF-κB and MAPK signaling pathways. Inflammation. 40:1–12. 2017.PubMed/NCBI View Article : Google Scholar
22	Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, et al: 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 62:147–239. 2013.PubMed/NCBI View Article : Google Scholar
23	Ye XH, Chen H, Yu Q and Zhu QL: Liver X receptor gene expression is enhanced in children with obstructive sleep apnea-hyperpnoea syndrome and cyclooxygenase-2 (COX-2) is correlated with severity of obstructive sleep apnea-hypopnea syndrome (OSAHS). Med Sci Monit. 23:3261–3268. 2017.PubMed/NCBI View Article : Google Scholar
24	Guo Z, Wang Y, Yang J, Zhong J, Liu X and Xu M: KAI1 overexpression promotes apoptosis and inhibits proliferation, cell cycle, migration, and invasion in nasopharyngeal carcinoma cells. Am J Otolaryngol. 38:511–517. 2017.PubMed/NCBI View Article : Google Scholar
25	Pathare AD and Deshpande AS: HGV-HCV/HBV co-infection in India: A pilot study. Asian J Transfus Sci. 7:48–50. 2013.PubMed/NCBI View Article : Google Scholar
26	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. 25:402–8. 2001.PubMed/NCBI View Article : Google Scholar
27	Yu X, Wang D, Wang X, Sun S, Zhang Y, Wang S, Miao R, Xu X and Qu X: CXCL12/CXCR4 promotes inflammation-driven colorectal cancer progression through activation of RhoA signaling by sponging miR-133a-3p. J Exp Clin Cancer Res. 38(32)2019.PubMed/NCBI View Article : Google Scholar
28	Burman D: Sleep disorders: Sleep-related breathing disorders. FP Essent. 460:11–21. 2017.PubMed/NCBI
29	Shenoda BB, Tian Y, Alexander GM, Aradillas-Lopez E, Schwartzman RJ and Ajit SK: miR-34a-mediated regulation of XIST in female cells under inflammation. J Pain Res. 11:935–945. 2018.PubMed/NCBI View Article : Google Scholar
30	Liu J, Yao L, Zhang M, Jiang J, Yang M and Wang Y: Downregulation of LncRNA-XIST inhibited development of non-small cell lung cancer by activating miR-335/SOD2/ROS signal pathway mediated pyroptotic cell death. Aging. 11:7830–7846. 2019.PubMed/NCBI View Article : Google Scholar
31	Wang J, Cai H, Dai Z and Wang G: Down-regulation of lncRNA XIST inhibits cell proliferation via regulating miR-744/RING1 axis in non-small cell lung cancer. Clin Sci (Lond). 133:1567–1579. 2019.PubMed/NCBI View Article : Google Scholar
32	Xing F, Liu Y, Wu SY, Wu K, Sharma S, Mo YY, Feng J, Sanders S, Jin G, Singh R, et al: Loss of XIST in breast cancer activates MSN-c-Met and reprograms microglia via exosomal miRNA to promote brain metastasis. Cancer Res. 78:4316–4330. 2018.PubMed/NCBI View Article : Google Scholar
33	Song YX, Ou YM and Zhou JY: Gracillin inhibits apoptosis and inflammation induced by lipopolysaccharide (LPS) to alleviate cardiac injury in mice via improving miR-29a. Biochem Biophys Res Commun. 523:580–587. 2020.PubMed/NCBI View Article : Google Scholar
34	Fu Z, Liao W, Ma H, Wang Z, Jiang M, Feng X and Zhang W: Inhibition of neddylation plays protective role in lipopolysaccharide-induced kidney damage through CRL-mediated NF-kappaB pathways. Am J Transl Res. 11:2830–2842. 2019.PubMed/NCBI
35	Zhao Y, Li S, Xia N, Shi Y and Zhao CM: Effects of XIST/miR-137 axis on neuropathic pain by targeting TNFAIP1 in a rat model. J Cell Physiol. 233:4307–4316. 2018.PubMed/NCBI View Article : Google Scholar
36	Zhang Y, Zhu Y, Gao G and Zhou Z: Knockdown XIST alleviates LPS-induced WI-38 cell apoptosis and inflammation injury via targeting miR-370-3p/TLR4 in acute pneumonia. Cell Biochem Funct. 37:348–358. 2019.PubMed/NCBI View Article : Google Scholar