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• W2999814618 abstract "Myasthenia gravis (MG) is an autoimmune disorder resulting from antibodies against the proteins at the neuromuscular junction. Emerging evidence indicates that long non-coding RNAs (lncRNAs), acting as competing endogenous RNAs (ceRNAs), are involved in various diseases. However, the regulatory mechanisms of ceRNAs underlying MG remain largely unknown. In this study, we constructed a lncRNA-mediated ceRNA network involved in MG using a multi-step computational strategy. Functional annotation analysis suggests that these lncRNAs may play crucial roles in the immunological mechanism underlying MG. Importantly, through manual literature mining, we found that lncRNA SNHG16 (small nucleolar RNA host gene 16), acting as a ceRNA, plays important roles in the immune processes. Further experiments showed that SNHG16 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from MG patients compared to healthy controls. Luciferase reporter assays confirmed that SNHG16 is a target of the microRNA (miRNA) let-7c-5p. Subsequent experiments indicated that SNHG16 regulates the expression of the key MG gene interleukin (IL)-10 by sponging let-7c-5p in a ceRNA manner. Furthermore, functional assays showed that SNHG16 inhibits Jurkat cell apoptosis and promotes cell proliferation by sponging let-7c-5p. Our study will contribute to a deeper understanding of the regulatory mechanism of MG and will potentially provide new therapeutic targets for MG patients. Myasthenia gravis (MG) is an autoimmune disorder resulting from antibodies against the proteins at the neuromuscular junction. Emerging evidence indicates that long non-coding RNAs (lncRNAs), acting as competing endogenous RNAs (ceRNAs), are involved in various diseases. However, the regulatory mechanisms of ceRNAs underlying MG remain largely unknown. In this study, we constructed a lncRNA-mediated ceRNA network involved in MG using a multi-step computational strategy. Functional annotation analysis suggests that these lncRNAs may play crucial roles in the immunological mechanism underlying MG. Importantly, through manual literature mining, we found that lncRNA SNHG16 (small nucleolar RNA host gene 16), acting as a ceRNA, plays important roles in the immune processes. Further experiments showed that SNHG16 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from MG patients compared to healthy controls. Luciferase reporter assays confirmed that SNHG16 is a target of the microRNA (miRNA) let-7c-5p. Subsequent experiments indicated that SNHG16 regulates the expression of the key MG gene interleukin (IL)-10 by sponging let-7c-5p in a ceRNA manner. Furthermore, functional assays showed that SNHG16 inhibits Jurkat cell apoptosis and promotes cell proliferation by sponging let-7c-5p. Our study will contribute to a deeper understanding of the regulatory mechanism of MG and will potentially provide new therapeutic targets for MG patients. Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies that attack proteins of the postsynaptic membrane at the neuromuscular junction, leading to muscle weakness and abnormal fatigability.1Gilhus N.E. Myasthenia gravis.N. Engl. J. Med. 2016; 375: 2570-2581Crossref PubMed Scopus (261) Google Scholar Most MG patients have detectable antibodies against the acetylcholine receptor (AChR), while a small group of patients have antibodies against muscle-specific kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4).2Gilhus N.E. Tzartos S. Evoli A. Palace J. Burns T.M. Verschuuren J.J.G.M. Myasthenia gravis.Nat. Rev. Dis. Primers. 2019; 5: 30Crossref PubMed Scopus (54) Google Scholar The production of antibodies is a T cell-dependent and B cell-mediated process. Cytokines produced by immune cells are crucial regulators of the pathogenesis of MG. For example, cytokines such as interleukin (IL)-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α secreted by T helper (Th) cells stimulate the production of pathogenic antibodies, which are mediated by B cells.3Conti-Fine B.M. Milani M. Kaminski H.J. Myasthenia gravis: past, present, and future.J. Clin. Invest. 2006; 116: 2843-2854Crossref PubMed Scopus (448) Google Scholar Moreover, both the expression of cytokines, such as IL-2, IFN-γ, and IL-10, and the number of peripheral blood mononuclear cells (PBMCs) secreting these cytokines are higher in patients with MG.4Huang Y.M. Kivisäkk P. Ozenci V. Pirskanen R. Link H. Increased levels of circulating acetylcholine receptor (AChR)-reactive IL-10-secreting cells are characteristic for myasthenia gravis (MG).Clin. Exp. Immunol. 1999; 118: 304-308Crossref PubMed Scopus (27) Google Scholar, 5Yapici Z. Tüzün E. Altunayoğlu V. Erdoğan A. Eraksoy M. High interleukin-10 production is associated with anti-acetylcholine receptor antibody production and treatment response in juvenile myasthenia gravis.Int. J. Neurosci. 2007; 117: 1505-1512Crossref PubMed Scopus (5) Google Scholar, 6Link J. Navikas V. Yu M. Fredrikson S. Osterman P.O. Link H. Augmented interferon-γ, interleukin-4 and transforming growth factor-β mRNA expression in blood mononuclear cells in myasthenia gravis.J. Neuroimmunol. 1994; 51: 185-192Abstract Full Text PDF PubMed Scopus (31) Google Scholar Increasing evidence shows that noncoding RNAs (ncRNAs) are involved in the regulation of gene expression in the immune system, and thus they provide novel insight into the pathogenesis, diagnosis, and treatment of MG.7Chen Y.G. Satpathy A.T. Chang H.Y. Gene regulation in the immune system by long noncoding RNAs.Nat. Immunol. 2017; 18: 962-972Crossref PubMed Scopus (260) Google Scholar Long ncRNAs (lncRNAs; more than 200 nt) interact with DNA, RNA, or proteins to modulate the expression of protein-coding genes, which play important roles in various biological processes, including the regulation of immune responses.7Chen Y.G. Satpathy A.T. Chang H.Y. Gene regulation in the immune system by long noncoding RNAs.Nat. Immunol. 2017; 18: 962-972Crossref PubMed Scopus (260) Google Scholar It has been reported that aberrant expression of lncRNA IFNG-AS1 in PBMCs regulates CD4+ T cell activation in MG patients partly by influencing human leukocyte antigen (HLA)-DRB1 expression.8Luo M. Liu X. Meng H. Xu L. Li Y. Li Z. Liu C. Luo Y.B. Hu B. Xue Y. et al.IFNA-AS1 regulates CD4+ T cell activation in myasthenia gravis though HLA-DRB1.Clin. Immunol. 2017; 183: 121-131Crossref PubMed Scopus (15) Google Scholar MicroRNAs (miRNAs; ∼22 nt) are small functional ncRNA molecules that repress target gene expression and are involved in a wide range of biological processes.9Jonas S. Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing.Nat. Rev. Genet. 2015; 16: 421-433Crossref PubMed Scopus (920) Google Scholar Accumulating evidence indicates that miRNAs contribute to the pathogenesis of MG by regulating important genes. For example, downregulation of miR-320a in MG patients induces inflammatory cytokine production by targeting mitogen-activated protein kinase 1 (MAPK1).10Cheng Z. Qiu S. Jiang L. Zhang A. Bao W. Liu P. Liu J. miR-320a is downregulated in patients with myasthenia gravis and modulates inflammatory cytokines production by targeting mitogen-activated protein kinase 1.J. Clin. Immunol. 2013; 33: 567-576Crossref PubMed Scopus (52) Google Scholar miR-15a is downregulated in MG patients and causes abnormal activation of the immune response by regulating IFN-γ-induced protein 10 (IP-10), which is a highly inducible chemoattractant causing secretion of more IFN-γ by activated Th1 cells.11Liu X.F. Wang R.Q. Hu B. Luo M.C. Zeng Q.M. Zhou H. Huang K. Dong X.H. Luo Y.B. Luo Z.H. Yang H. miR-15a contributes abnormal immune response in myasthenia gravis by targeting CXCL10.Clin. Immunol. 2016; 164: 106-113Crossref PubMed Scopus (23) Google Scholar Although some miRNAs and lncRNAs have been found to be implicated in MG, few studies have focused on exploring the interactions among miRNAs, lncRNAs, and genes underlying the pathogenesis of MG. Recently, the competing endogenous RNA (ceRNA) theory was proposed, pointing out that RNA molecules containing miRNA response elements (MREs) could compete with each other by binding to a common miRNA.12Salmena L. Poliseno L. Tay Y. Kats L. Pandolfi P.P. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?.Cell. 2011; 146: 353-358Abstract Full Text Full Text PDF PubMed Scopus (3520) Google Scholar There is increasing evidence that lncRNAs function as ceRNAs, competing with mRNAs by acting as sponges of miRNAs, which relieve miRNA-mediated target repression.13Wang P. Zhi H. Zhang Y. Liu Y. Zhang J. Gao Y. Guo M. Ning S. Li X. miRSponge: a manually curated database for experimentally supported miRNA sponges and ceRNAs.Database (Oxford). 2015; 2015: bav098Crossref PubMed Scopus (65) Google Scholar lncRNAs, acting as ceRNAs, are implicated in various diseases. For example, the lncRNA ZNFX1-AS1 has been shown to play an important role in the progression and metastasis of colorectal cancer by acting as a ceRNA of miR-144, thereby leading to the depression of its endogenous target gene polycomb group protein enhancer of zeste homolog 2 (EZH2).14Shi L. Hong X. Ba L. He X. Xiong Y. Ding Q. Yang S. Peng G. Long non-coding RNA ZNFX1-AS1 promotes the tumor progression and metastasis of colorectal cancer by acting as a competing endogenous RNA of miR-144 to regulate EZH2 expression.Cell Death Dis. 2019; 10: 150Crossref PubMed Scopus (31) Google Scholar Additionally, lncRNAs, acting as ceRNAs, also play crucial roles in the regulation of the immune system and the development of autoimmune diseases. lncRNA MEG3 regulates RORγt expression by sequestering miR-17, which affects the regulatory T (Treg)/Th17 balance in asthma.15Qiu Y.Y. Wu Y. Lin M.J. Bian T. Xiao Y.L. Qin C. LncRNA-MEG3 functions as a competing endogenous RNA to regulate Treg/Th17 balance in patients with asthma by targeting microRNA-17/RORγt.Biomed. Pharmacother. 2019; 111: 386-394Crossref PubMed Scopus (43) Google Scholar Despite advances in ceRNA regulation, their potential roles in MG remain largely unknown. Thus, there is an urgent need to explore the ceRNA regulatory mechanism of MG and to develop novel biomarkers for the diagnosis and treatment of MG. In the present study, we first constructed a global lncRNA-mediated ceRNA network involved in MG using a multi-step computational approach. Functional enrichment analysis was performed to reveal the potential roles of these lncRNAs in the network. Through analyzing the network and reviewing reliable publications, we designed biological experiments to further confirm the presence of an SNHG16 (small nucleolar RNA host gene 16)-mediated ceRNA regulatory mechanism through the let-7c-5p/IL-10 axis in MG. Our study provides novel insights into the ceRNA network and reveals potential roles of SNHG16 in MG. It is well known that lncRNAs can act as ceRNAs by binding miRNAs.13Wang P. Zhi H. Zhang Y. Liu Y. Zhang J. Gao Y. Guo M. Ning S. Li X. miRSponge: a manually curated database for experimentally supported miRNA sponges and ceRNAs.Database (Oxford). 2015; 2015: bav098Crossref PubMed Scopus (65) Google Scholar To evaluate the lncRNA-mediated ceRNA regulation in MG, an lncRNA-mediated MG-associated ceRNA network (LMGCN) was constructed using a multi-step approach (Figure 1A). As a result, the LMGCN contained 9 miRNAs, 20 genes, 32 lncRNAs, and 147 edges (Figure 1B). We referred to the previous study16Jiang H. Ma R. Zou S. Wang Y. Li Z. Li W. Reconstruction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in rheumatoid arthritis.Mol. Biosyst. 2017; 13: 1182-1192Crossref PubMed Google Scholar to count the number of the primary relationship pairs of lncRNA-miRNA and the secondary relationship pairs of miRNA-mRNA (Table S1). For a given lncRNA(i), the number of the primary relationship pairs of lncRNA-miRNA represents the number of miRNAs linked with lncRNA(i), and the number of the secondary relationship pairs of miRNA-mRNA represents the sum of mRNAs linked with the above miRNAs. HELLPAR had the highest total number of lncRNA-miRNA and miRNA-mRNA pairs, which may play important roles in the network. To further explore the roles of lncRNAs, we first used RNALocate17Zhang T. Tan P. Wang L. Jin N. Li Y. Zhang L. Yang H. Hu Z. Zhang L. Hu C. et al.RNALocate: a resource for RNA subcellular localizations.Nucleic Acids Res. 2017; 45: D135-D138PubMed Google Scholar to investigate the subcellular localization of each lncRNA in the LMGCN (Table S2). RNALocate is a comprehensive database that provides experimentally supported high-quality RNA subcellular localizations. Then, we performed functional annotation analysis using the co-expressed mRNA. 58 pathways and 113 Gene Ontology (GO) terms were identified (p < 0.05). Moreover, more than one third of the identified terms and pathways are relevant to immune or inflammatory mechanism (Table S3). We mainly listed several immune-related GO functions and pathways that play important roles in the immunological mechanism of MG (Figure 1C). For example, the significant GO functions included immune response, positive regulation of B cell proliferation, thymus development, positive regulation of T cell proliferation, and inflammatory response. The significant pathways included cytokine-cytokine receptor interaction, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. These findings highlighted the fundamental characteristics of these lncRNAs in the pathogenesis of MG. Based on the LMGCN, four miRNA-gene regulation pairs had reportedly been verified in MG: let-7c-5p/IL-10,18Jiang L. Cheng Z. Qiu S. Que Z. Bao W. Jiang C. Zou F. Liu P. Liu J. Altered let-7 expression in myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells.Int. Immunopharmacol. 2012; 14: 217-223Crossref PubMed Scopus (47) Google Scholar miR-145-5p/CD28,19Sengupta M. Wang B.D. Lee N.H. Marx A. Kusner L.L. Kaminski H.J. MicroRNA and mRNA expression associated with ectopic germinal centers in thymus of myasthenia gravis.PLoS ONE. 2018; 13: e0205464Crossref PubMed Scopus (8) Google Scholar miR-15a-5p/CXCL10,11Liu X.F. Wang R.Q. Hu B. Luo M.C. Zeng Q.M. Zhou H. Huang K. Dong X.H. Luo Y.B. Luo Z.H. Yang H. miR-15a contributes abnormal immune response in myasthenia gravis by targeting CXCL10.Clin. Immunol. 2016; 164: 106-113Crossref PubMed Scopus (23) Google Scholar and miR-181c-5p/IL7.20Zhang Y. Guo M. Xin N. Shao Z. Zhang X. Zhang Y. Chen J. Zheng S. Fu L. Wang Y. et al.Decreased microRNA miR-181c expression in peripheral blood mononuclear cells correlates with elevated serum levels of IL-7 and IL-17 in patients with myasthenia gravis.Clin. Exp. Med. 2016; 16: 413-421Crossref PubMed Scopus (16) Google Scholar We extracted the sub-networks of these four miRNA-gene pairs and their linked lncRNAs in the global triple network. We found eight lncRNAs that may act as ceRNAs to regulate the miRNA-gene pairs mentioned above. Through reviewing reliable publications, we summarized the functions of these lncRNAs (Figure 2; the detailed information is summarized in Table S4). These lncRNAs are mainly involved in the development of various cancers,21Liu Z.B. Tang C. Jin X. Liu S.H. Pi W. Increased expression of lncRNA SNHG12 predicts a poor prognosis of nasopharyngeal carcinoma and regulates cell proliferation and metastasis by modulating Notch signal pathway.Cancer Biomark. 2018; 23: 603-613Crossref PubMed Scopus (26) Google Scholar, 22Wen Q. Zhao L. Wang T. Lv N. Cheng X. Zhang G. Bai L. lncRNA SNHG16 drives proliferation and invasion of papillary thyroid cancer through modulation of miR-497.OncoTargets Ther. 2019; 12: 699-708Crossref PubMed Scopus (22) Google Scholar, 23Luan F. Chen W. Chen M. Yan J. Chen H. Yu H. Liu T. Mo L. An autophagy-related long non-coding RNA signature for glioma.FEBS Open Bio. 2019; 9: 653-667Crossref PubMed Scopus (45) Google Scholar with other functions including immune processes,24Wang W. Lou C. Gao J. Zhang X. Du Y. lncRNA SNHG16 reverses the effects of miR-15a/16 on LPS-induced inflammatory pathway.Biomed. Pharmacother. 2018; 106: 1661-1667Crossref PubMed Scopus (30) Google Scholar neuroprotective effects in ischemia/reperfusion injury,25Yao X. Yao R. Huang F. Yi J. lncRNA SNHG12 as a potent autophagy inducer exerts neuroprotective effects against cerebral ischemia/reperfusion injury.Biochem. Biophys. Res. Commun. 2019; 514: 490-496Crossref PubMed Scopus (26) Google Scholar and vascular calcification.26Jeong G. Kwon D.H. Shin S. Choe N. Ryu J. Lim Y.H. Kim J. Park W.J. Kook H. Kim Y.K. Long noncoding RNAs in vascular smooth muscle cells regulate vascular calcification.Sci. Rep. 2019; 9: 5848Crossref PubMed Scopus (14) Google Scholar More importantly, SNHG16 acting as a ceRNA was reported to be involved in inflammatory and immune processes24Wang W. Lou C. Gao J. Zhang X. Du Y. lncRNA SNHG16 reverses the effects of miR-15a/16 on LPS-induced inflammatory pathway.Biomed. Pharmacother. 2018; 106: 1661-1667Crossref PubMed Scopus (30) Google Scholar that may participate in the pathogenesis of MG. We found that SNHG16 potentially competed with IL-10 in the sub-network. IL-10 is an important growth factor for B cells, augmenting B cells activation into antibody-producing cells, and it plays important roles in the pathogenesis of MG.4Huang Y.M. Kivisäkk P. Ozenci V. Pirskanen R. Link H. Increased levels of circulating acetylcholine receptor (AChR)-reactive IL-10-secreting cells are characteristic for myasthenia gravis (MG).Clin. Exp. Immunol. 1999; 118: 304-308Crossref PubMed Scopus (27) Google Scholar These findings suggest that the IL-10/SNHG16 competing pair might be involved in the immunological pathogenesis of MG. Therefore, we primarily focused on SNHG16/let-7c-5p/IL-10 interaction for further experimental verification. Real-time PCR analysis was performed to examine lncRNA SNHG16 in PBMCs from MG patients and control subjects. The expression of SNHG16 was higher in patients with MG compared with controls (p = 0.004, Figure 3A). Bioinformatics analysis revealed that the SNHG16 sequence contains a putative let-7c-5p binding region. A previous study had indicated that let-7c-5p was downregulated in PBMCs of MG patients.18Jiang L. Cheng Z. Qiu S. Que Z. Bao W. Jiang C. Zou F. Liu P. Liu J. Altered let-7 expression in myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells.Int. Immunopharmacol. 2012; 14: 217-223Crossref PubMed Scopus (47) Google Scholar To investigate the association between let-7c-5p and SNHG16, let-7c-5p mimics were transfected into Jurkat cells. The transfection efficiency of let-7c-5p mimics was confirmed by real-time PCR (p = 0.0003, Figure 3B). Overexpression of let-7c-5p significantly inhibited the expression of SNHG16 in Jurkat cells (p < 0.01, Figure 3C). To further confirm the direct interaction between SNHG16 and let-7c-5p, we constructed luciferase reporter vectors of SNHG16-wild type (WT) and SNHG16-mutated type (MUT) (Figure 3D). The SNHG16-WT or SNHG16-MUT was then co-transfected with let-7c-5p mimics or negative control into HEK293T cells. The dual-luciferase reporter assay showed that let-7c-5p mimics suppressed the luciferase activity of SNHG16-WT but had no effect on the luciferase activity of SNHG16-MUT (Figure 3E). These results indicated that SNHG16 is the target of let-7c-5p. MG is a T cell-dependent and B cell-mediated autoimmune disease. Cytokines play an important role in the regulation of autoantibody production and cell-mediated immunity in MG.2Gilhus N.E. Tzartos S. Evoli A. Palace J. Burns T.M. Verschuuren J.J.G.M. Myasthenia gravis.Nat. Rev. Dis. Primers. 2019; 5: 30Crossref PubMed Scopus (54) Google Scholar It has been reported that there is a negative correlation between let-7c-5p and IL-10 mRNA levels in MG patients, and that let-7c-5p mediates regulation of IL-10 by directly targeting IL-10 in Jurkat cells.18Jiang L. Cheng Z. Qiu S. Que Z. Bao W. Jiang C. Zou F. Liu P. Liu J. Altered let-7 expression in myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells.Int. Immunopharmacol. 2012; 14: 217-223Crossref PubMed Scopus (47) Google Scholar Therefore, we designed experiments to explore whether SNHG16 could regulate IL-10 expression by targeting let-7c-5p. First, we measured the expression of IL-10 mRNA and protein in Jurkat cells after transfection with let-7c-5p mimics or negative control. The results indicated that let-7c-5p overexpression decreased IL-10 expression at both the mRNA and protein level (p < 0.01, Figures 4A and 4B ), which was consistent with the results of a previous study.18Jiang L. Cheng Z. Qiu S. Que Z. Bao W. Jiang C. Zou F. Liu P. Liu J. Altered let-7 expression in myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells.Int. Immunopharmacol. 2012; 14: 217-223Crossref PubMed Scopus (47) Google Scholar To verify whether SNHG16 regulates IL-10 expression by targeting let-7c-5p, Jurkat cells were transfected with negative control, siSNHG16, and siSNHG16 in combination with let-7c-5p inhibitor. Then, the IL-10 mRNA and protein levels were determined. The results showed that knockdown of SNHG16 suppressed the IL-10 mRNA and protein expression levels in Jurkat cells, whereas let-7c-5p inhibitor blocked the reduction in IL-10 expression induced by SNHG16 suppression (p < 0.01, Figures 4C and 4D). These findings suggest that SNHG16 regulates the expression of IL-10 by sponging let-7c-5p in a ceRNA manner. MG is a T cell-dependent autoimmune disease, and the proliferation and activation of T cells play an important role in the pathogenesis of MG. Therefore, we used Jurkat T cells for functional verification of MG, referring to previous studies.10Cheng Z. Qiu S. Jiang L. Zhang A. Bao W. Liu P. Liu J. miR-320a is downregulated in patients with myasthenia gravis and modulates inflammatory cytokines production by targeting mitogen-activated protein kinase 1.J. Clin. Immunol. 2013; 33: 567-576Crossref PubMed Scopus (52) Google Scholar,18Jiang L. Cheng Z. Qiu S. Que Z. Bao W. Jiang C. Zou F. Liu P. Liu J. Altered let-7 expression in myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells.Int. Immunopharmacol. 2012; 14: 217-223Crossref PubMed Scopus (47) Google Scholar To determine whether SNHG16 affects apoptosis and proliferation of Jurkat cells by targeting let-7c-5p, Jurkat cells were transfected with negative control, siSNHG16, and siSNHG16 along with let-7c-5p inhibitor. Then, flow cytometry and a Cell Counting Kit-8 (CCK-8) assay were used to assess the rates of apoptosis and proliferation. The rate of apoptosis increased following transfection with siSNHG16, whereas the addition of let-7c-5p inhibitor abrogated the above trend (p < 0.01, Figures 5A and 5B ). Moreover, the CCK-8 assay revealed that knockdown of SNHG16 inhibited proliferation of Jurkat cells compared with transfection with negative control, and this effect was reversed by transfecting with let-7c-5p inhibitor (p < 0.01, Figure 5C). These results suggest that SNHG16 inhibits cell apoptosis and promotes proliferation by sponging let-7c-5p in Jurkat cells. Taken together, our results suggest that SNHG16 regulates T cell apoptosis and proliferation by sponging let-7c-5p, which is involved in the immunological pathogenesis of MG (Figure 5D). MG is a neurological autoantibody-mediated disease, but the triggering autoimmune processes involved are not clearly defined. Immunomodulatory therapies have been widely used to improve the prognosis for MG patients. Given the complex pathogenesis and heterogeneity of MG, no one treatment therapy is best for all MG patients.27Sanders D.B. Wolfe G.I. Benatar M. Evoli A. Gilhus N.E. Illa I. Kuntz N. Massey J.M. Melms A. Murai H. et al.International consensus guidance for management of myasthenia gravis: executive summary.Neurology. 2016; 87: 419-425Crossref PubMed Scopus (327) Google Scholar Extensive evidence indicates that lncRNAs play critical roles in regulation of the immune system and in autoimmune disease.7Chen Y.G. Satpathy A.T. Chang H.Y. Gene regulation in the immune system by long noncoding RNAs.Nat. Immunol. 2017; 18: 962-972Crossref PubMed Scopus (260) Google Scholar The recently uncovered lncRNA-mediated ceRNA regulatory theory and networks improve our understanding of the precise molecular mechanism of MG. During the past few years, ceRNA regulatory mechanisms have been validated in various diseases. To date, several databases have been developed to curate ceRNA interactions based on experimentally supported evidence or computationally predicted methods, such as LncACTdb,28Wang P. Li X. Gao Y. Guo Q. Wang Y. Fang Y. Ma X. Zhi H. Zhou D. Shen W. et al.LncACTdb 2.0: an updated database of experimentally supported ceRNA interactions curated from low- and high-throughput experiments.Nucleic Acids Res. 2019; 47: D121-D127Crossref PubMed Scopus (42) Google Scholar starBase,29Li J.H. Liu S. Zhou H. Qu L.H. Yang J.H. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-seq data.Nucleic Acids Res. 2014; 42: D92-D97Crossref PubMed Scopus (1954) Google Scholar and PceRBase30Yuan C. Meng X. Li X. Illing N. Ingle R.A. Wang J. Chen M. PceRBase: a database of plant competing endogenous RNA.Nucleic Acids Res. 2017; 45: D1009-D1014Crossref PubMed Scopus (30) Google Scholar. MNDR v2.031Cui T. Zhang L. Huang Y. Yi Y. Tan P. Zhao Y. Hu Y. Xu L. Li E. Wang D. MNDR v2.0: an updated resource of ncRNA-disease associations in mammals.Nucleic Acids Res. 2018; 46: D371-D374PubMed Google Scholar and RAID v2.032Yi Y. Zhao Y. Li C. Zhang L. Huang H. Li Y. Liu L. Hou P. Cui T. Tan P. et al.RAID v2.0: an updated resource of RNA-associated interactions across organisms.Nucleic Acids Res. 2017; 45: D115-D118Crossref PubMed Scopus (141) Google Scholar are also useful resources for analyzing RNA-disease associations. These databases are valuable resources for studying ceRNA regulation underlying complex diseases. However, so far, most studies concerning ceRNA network construction and mechanisms have focused on the cancer field. For example, Wang et al.33Wang P. Ning S. Zhang Y. Li R. Ye J. Zhao Z. Zhi H. Wang T. Guo Z. Li X. Identification of lncRNA-associated competing triplets reveals global patterns and prognostic markers for cancer.Nucleic Acids Res. 2015; 43: 3478-3489Crossref PubMed Scopus (159) Google Scholar constructed a lncRNA-associated ceRNA network to reveal global patterns and prognostic markers across 12 types of human cancer. However, only a few ceRNA interactions have been reported in autoimmune diseases.16Jiang H. Ma R. Zou S. Wang Y. Li Z. Li W. Reconstruction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in rheumatoid arthritis.Mol. Biosyst. 2017; 13: 1182-1192Crossref PubMed Google Scholar Accordingly, there is a need to explore the regulatory mechanisms of ceRNAs in MG. In the present study, we first constructed an LMGCN based on the ceRNA theory using a comprehensive approach. The LMGCN was composed of 9 miRNA nodes, 20 mRNA nodes, and 32 lncRNA nodes. The results of functional annotation analysis suggest that these lncRNAs may play crucial roles in the development of MG. Next, we summarized the functions of lncRNA as a ceRNA to regulate miRNA-gene interactions that have been verified in MG. Of note, a recent study showed that SNHG16 affected the LPS-induced inflammatory and immune processes. Subsequently, mechanistic investigations revealed that SHNG16 acts as a ceRNA to positively regulate Toll-like receptor 4 (TLR4) by competitively binding miR-15a/16.24Wang W. Lou C. Gao J. Zhang X. Du Y. lncRNA SNHG16 reverses the effects of miR-15a/16 on LPS-induced inflammatory pathway.Biomed. Pharmacother. 2018; 106: 1661-1667Crossref PubMed Scopus (30) Google Scholar Indeed, growing evidence shows that SNHG16 serving as a ceRNA is involved in several diseases.34Wang X. Kan J. Han J. Zhang W. Bai L. Wu H. lncRNA SNHG16 functions as an oncogene by sponging miR-135a and promotes JAK2/STAT3 signal pathway in gastric cancer.J. Cancer. 2019; 10: 1013-1022Crossref PubMed Scopus (47) Google Scholar,35Lin Q. Zheng H. Xu J. Zhang F. Pan H. lncRNA SNHG16 aggravates tumorigenesis and development of hepatocellular carcinoma by sponging miR-4500 and targeting STAT3.J. Cell. Biochem. 2019; 120: 11604-11615Crossref Scopus (26) Google Scholar However, the underlying mechanism of the involvement of SNHG16 in MG remains unclear. The present study found that SNHG16 expression is increased in PBMCs from MG patients. Functionally, we found that knockdown of SNHG16 suppresses cell proliferation and promotes apoptosis in Jurkat cells. These results suggest that SNHG16 might be involved in the immunological pathogenesis of MG. Bioinformatics analysis predicted that SNHG16 was a direct target of let-7c-5p. A previous study has reported that let-7c-5p is downregulated in PBMCs from MG patients, and that IL-10 is a target for let-7c-5p. Meanwhile, let-7c regulates IL-10 secretion in Jurkat cells.18Jiang L. Cheng Z. Qiu S. Que Z. Bao W. Jiang C. Zou F. Liu P. Liu J. Altered let-7 expression in myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells.Int. Immunopharmacol. 2012; 14: 217-223Crossref PubMed Scopus (47) Google Scholar We found that let-7c-5p overexpression decreased IL-10 mRNA and protein expression levels in Jurkat cells, findings that were consistent with the results of previous study. Hence, we hypothesized that SHNG16 acted as a ceRNA to regulate the let-7c-5p/IL-10 axis in MG (Figure 5D). We foun" @default.
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• W2999814618 title "Identification of the Regulatory Role of lncRNA SNHG16 in Myasthenia Gravis by Constructing a Competing Endogenous RNA Network" @default.
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• W2999814618 doi "https://doi.org/10.1016/j.omtn.2020.01.005" @default.
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