Construction of Predictive CeRNA Network and Identification of the Patterns of Immune Cells Infiltrated in Graves Ophthalmopathy

Overview

Journal Zhong Nan Da Xue Xue Bao Yi Xue Ban

Specialty General Medicine

Date 2023 Oct 24

PMID 37875358

Authors

JiaMin Cao

Haiyan Chen

Bingyu Xie

Yizhi Chen

Wei Xiong

Mingyuan Li

Affiliations

Soon will be listed here.

Abstract

Objectives: Graves' ophthalmopathy (GO) is a multifactorial disease, and the mechanism of non coding RNA interactions and inflammatory cell infiltration patterns are not fully understood. This study aims to construct a competing endogenous RNA (ceRNA) network for this disease and clarify the infiltration patterns of inflammatory cells in orbital tissue to further explore the pathogenesis of GO.

Methods: The differentially expressed genes were identified using the GEO2R analysis tool. The Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology analysis were used to analyze differential genes. RNA interaction relationships were extracted from the RNA interactome database. Protein-protein interactions were identified using the STRING database and were visualized using Cytoscape. StarBase, miRcode, and DIANA-LncBase Experimental v.2 were used to construct ceRNA networks together with their interacted non-coding RNA. The CIBERSORT algorithm was used to detect the patterns of infiltrating immune cells in GO using R software.

Results: A total of 114 differentially expressed genes for GO and 121 pathways were detected using both the KEGG and gene ontology enrichment analysis. Four hub genes (,and ) were extracted from protein-protein interaction using cytoHubba in Cytoscape, 104 nodes and 142 edges were extracted, and a ceRNA network was identified (). The results of immune cell analysis showed that in GO, the proportions of CD8 T cells and CD4 memory resting T cells were upregulated and downregulated, respectively. The proportion of CD4 memory resting T cells was positively correlated with the expression of .

Conclusions: This study has constructed a ceRNA regulatory network (MALAT1-MIR21-DDX5) in GO orbital tissue, clarifying the downregulation of the proportion of CD4 stationary memory T cells and their positive regulatory relationship with ceRNA components, further revealing the pathogenesis of GO.

Citing Articles

The relationship of peripheral blood lncRNA-PVT1 and miR-146a levels with Th17/Treg cytokines in patients with Hashimoto's thyroiditis and their clinical significance.

Li Y, Shen J, Feng Y, Zhang Y, Wang Y, Ren X Biomol Biomed. 2024; 24(5):1170-1177.

PMID: 38761409 PMC: 11379023. DOI: 10.17305/bb.2024.10237.

References

. [Chinese guideline on the diagnosis and treatment of thyroid-associated ophthalmopathy (2022)]. Zhonghua Yan Ke Za Zhi. 2022; 58(9):646-668. DOI: 10.3760/cma.j.cn112142-20220421-00201. View

Smith T, Janssen J . Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy. Endocr Rev. 2018; 40(1):236-267. PMC: 6338478. DOI: 10.1210/er.2018-00066. View

Han J, Shen L, Zhan Z, Liu Y, Zhang C, Guo R . The long noncoding RNA MALAT1 modulates adipose loss in cancer-associated cachexia by suppressing adipogenesis through PPAR-γ. Nutr Metab (Lond). 2021; 18(1):27. PMC: 7944636. DOI: 10.1186/s12986-021-00557-0. View

Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi P . A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?. Cell. 2011; 146(3):353-8. PMC: 3235919. DOI: 10.1016/j.cell.2011.07.014. View

Wang J, Zhu Z, Qiu H, Liu C, Chang X, Qi Y . LncRNA NKILA inhibits the proliferation and promotes the apoptosis of CSCC cells by downregulating miRNA-21. J Cell Physiol. 2020; 235(11):7863-7869. DOI: 10.1002/jcp.29439. View

Kong N, Bao Y, Zhao H, Kang X, Tai X, Chen X . Long Noncoding RNA LINC01518 Modulates Proliferation and Migration in TGF-β1-Treated Human Tenon Capsule Fibroblast Cells Through the Regulation of hsa-miR-216b-5p. Neuromolecular Med. 2021; 24(2):88-96. DOI: 10.1007/s12017-021-08662-2. View

Yang L, Lin C, Liu Z . P68 RNA helicase mediates PDGF-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. Cell. 2006; 127(1):139-55. DOI: 10.1016/j.cell.2006.08.036. View

Zhang X, Hamblin M, Yin K . The long noncoding RNA Malat1: Its physiological and pathophysiological functions. RNA Biol. 2017; 14(12):1705-1714. PMC: 5731810. DOI: 10.1080/15476286.2017.1358347. View

Smith T, Hegedus L . Graves' Disease. N Engl J Med. 2016; 375(16):1552-1565. DOI: 10.1056/NEJMra1510030. View

10.

Lee J, Yun M, Paik J, Lee S, Yang S . PDGF-BB Enhances the Proliferation of Cells in Human Orbital Fibroblasts by Suppressing PDCD4 Expression Via Up-Regulation of microRNA-21. Invest Ophthalmol Vis Sci. 2016; 57(3):908-13. DOI: 10.1167/iovs.15-18157. View

11.

Shih S, Liao S, Shih C, Wei Y, Lu T, Chou C . Fibroblast Growth Factor Receptor Inhibitors Reduce Adipogenesis of Orbital Fibroblasts and Enhance Myofibroblastic Differentiation in Graves' Orbitopathy. Ocul Immunol Inflamm. 2019; 29(1):193-202. DOI: 10.1080/09273948.2019.1672196. View

12.

Wang Y, Wang L, Guo H, Peng Y, Nie D, Mo J . Knockdown of MALAT1 attenuates high-glucose-induced angiogenesis and inflammation via endoplasmic reticulum stress in human retinal vascular endothelial cells. Biomed Pharmacother. 2020; 124:109699. DOI: 10.1016/j.biopha.2019.109699. View

13.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

14.

Al-Ansari F, Lahooti H, Stokes L, Edirimanne S, Wall J . Correlation between thyroidal and peripheral blood total T cells, CD8 T cells, and CD8 T- regulatory cells and T-cell reactivity to calsequestrin and collagen XIII in patients with Graves' ophthalmopathy. Endocr Res. 2018; 43(4):264-274. DOI: 10.1080/07435800.2018.1470639. View

15.

Hu Z, He J, Li K, Chen J, Xie X . Decreased microRNA-146a in CD4+T cells promote ocular inflammation in thyroid-associated ophthalmopathy by targeting NUMB. Eur Rev Med Pharmacol Sci. 2017; 21(8):1803-1809. View

16.

Newman A, Liu C, Green M, Gentles A, Feng W, Xu Y . Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015; 12(5):453-7. PMC: 4739640. DOI: 10.1038/nmeth.3337. View

17.

Martinez-Hernandez R, Sampedro-Nunez M, Serrano-Somavilla A, Ramos-Levi A, de la Fuente H, Trivino J . A MicroRNA Signature for Evaluation of Risk and Severity of Autoimmune Thyroid Diseases. J Clin Endocrinol Metab. 2018; 103(3):1139-1150. DOI: 10.1210/jc.2017-02318. View

18.

Jia H, Zhang K, Lu W, Xu G, Zhang J, Tang Z . LncRNA MEG3 influences the proliferation and apoptosis of psoriasis epidermal cells by targeting miR-21/caspase-8. BMC Mol Cell Biol. 2019; 20(1):46. PMC: 6816225. DOI: 10.1186/s12860-019-0229-9. View

19.

Wang N, Chen F, Long Z . Mechanism of MicroRNA-146a/Notch2 Signaling Regulating IL-6 in Graves Ophthalmopathy. Cell Physiol Biochem. 2017; 41(4):1285-1297. DOI: 10.1159/000464430. View

20.

Li A, Yang J, Zhang T, Li L, Li M . Long Noncoding RNA TRPM2-AS Promotes the Growth, Migration, and Invasion of Retinoblastoma via miR-497/WEE1 Axis. Front Pharmacol. 2021; 12:592822. PMC: 8112210. DOI: 10.3389/fphar.2021.592822. View