山东大学耳鼻喉眼学报 ›› 2025, Vol. 39 ›› Issue (4): 151-160.doi: 10.6040/j.issn.1673-3770.0.2024.161

• 论著 • 上一篇    下一篇

miRNA-mRNA网络参与高脂饮食损伤甲状腺功能的生物信息学分析

窦涛1,窦乃馨1,汪如1,杨芊1,管庆波1,王磊2,于春晓1   

  1. 1. 内分泌糖脂代谢与脑老化教育部重点实验室, 山东第一医科大学附属省立医院内分泌代谢病科, 山东省内分泌与脂代谢重点实验室, 山东 济南 250021;
    2. 山东第一医科大学附属中心医院 胃肠外科, 山东 济南 250021
  • 出版日期:2025-07-20 发布日期:2025-08-11
  • 通讯作者: 于春晓. E-mail:yuchx08@163.com

Bioinformatic analysis of miRNA-mRNA network involved in thyroid function impairment by high-fat diet

DOU Tao1, DOU Naixin1, WANG Ru1, YANG Qian1, GUAN Qingbo1, WANG Lei2, YU Chunxiao1   

  1. 1. Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan 250021, Shandong, China2. Department of Gastroenterology, Affiliated Central Hospital of Shandong First Medical University, Jinan 250021, Shandong, China
  • Online:2025-07-20 Published:2025-08-11

PDF (PC)

29

摘要： 目的 通过生物信息学方法分析参与高脂饮食损伤甲状腺功能的miRNA-mRNA调控网络,为早期干预脂毒性损伤甲状腺功能提供新的靶点。 方法 给予大鼠高脂饮食8周,建立甲状腺功能损伤大鼠模型,以正常饮食组为对照,Agilent芯片检测甲状腺miRNA和mRNA表达,RStudio的limma包筛选差异miRNA和mRNA。miRwalk预测差异miRNA调控的潜在下游靶基因,利用微生信网站将预测的靶基因和差异mRNA取交集,建立差异miRNA-差异mRNA网络。通过在线网站Metascape对交集mRNA进行基因本体论(gene ontology, GO)注释和京都基因和基因组百科全书(kyoto encyclopedia of genes and genomes, KEGG)通路分析。利用String在线网站进行蛋白质-蛋白质相互作用(protein-protein interaction, PPI)分析,使用Cytoscape可视化PPI网络,CytoNCA插件筛选枢纽基因。基于关键基因建立高脂饮食损伤甲状腺功能的潜在miRNA-mRNA网络。 结果 筛选出27个上调和6个下调miRNA,775个上调和543个下调mRNA,下调miRNA的靶点mRNA与芯片筛选的上调mRNA有301个重叠,上调miRNA的靶点mRNA与芯片筛选的下调mRNA有278个重叠,分别获得491和777个miRNA-mRNA对。GO和KEGG分析发现差异mRNA富集到与甲状腺激素合成和细胞增殖等相关通路。进一步筛选出Src、Pebp1、Il1b、Plcg1、Igf1、Ntrk2等10个枢纽基因,建立了包括miR-3473/Src、miR-339-3p/Igf1、miR-674-5p/Igf1、miR-339-3p/Ntrk2、miR-99b-3p/Ntrk2等的关键miRNA-mRNA调控对。 结论 miR-3473、Igf1和Ntrk2等可能作为核心miRNA和mRNA,参与调控高脂饮食损伤甲状腺功能。

关键词: 甲状腺功能减退, 高脂饮食, miRNA-mRNA网络

Abstract: Objective To analyze the miRNA-mRNA regulatory network involved in high-fat diet-induced damage to thyroid function using bioinformatics methods, and to provide new targets for early intervention in lipid toxicity-induced thyroid dysfunction. Methods Rats were fed a high-fat diet for 8 weeks to establish a model of thyroid function damage, with a normal diet group as control. Agilent chips were used to detect thyroid miRNA and mRNA expression, and the “limma” package in RStudio was used to screen for differentially expressed miRNA and mRNA. The miRwalk was used to predict potential downstream target genes regulated by differentially expressed miRNA. The predicted target genes and differentially expressed mRNA were intersected using weishengxin websites to establish a differential miRNA-mRNA network. Gene ontology(GO)annotation and kyoto encyclopedia of genes and genomes(KEGG)pathway analysis of the intersected mRNA were performed using the Metascape website. protein-protein interaction(PPI)analysis was conducted using the String online platform, and the PPI network hub was visualized using Cytoscape,hub genes were selected using the CytoNCA plugin in Cytoscape. A potential miRNA-mRNA network affecting thyroid function due to high-fat diet was established based on the selected hub genes. Results 27 upregulated and 6 downregulated miRNAs, 775 upregulated and 543 downregulated mRNAs were screened, with 301 overlapping mRNAs between downregulated miRNA targets and upregulated mRNAs, and 278 overlapping mRNAs between upregulated miRNA targets and downregulated mRNAs, resulting in 491 and 777 miRNA-mRNA pairs, respectively. GO and KEGG analysis revealed that differential mRNAs were enriched in pathways related to thyroid hormone synthesis and cell proliferation. Further screening identified 10 hub genes including Src, Pebp1, Il1b, Plcg1, Igf1, etc. A key miRNA-mRNA regulatory network was established based on these hub genes, including regulatory pairs such as miR-3473/Src、miR-339-3p/Igf1、miR-674-5p/Igf1、miR-339-3p/Ntrk2、miR-99b-3p/Ntrk2. Conclusion The miRNA and mRNA, such as miR-3473、Igf1 and Ntrk2 may be involved in high-fat diet-induced damage to thyroid function.

Key words: Hypothyroidism, High-fat diet, miRNA-mRNA network

中图分类号: 

  • R581.2
[1] 马世瞻, 赵家军. 内分泌与脂代谢[J]. 华西医学, 2018, 33(5): 491-498. doi:10.7507/1002-0179.201804027 MA Shizhan, ZHAO Jiajun. Endocrinology and lipid metabolism[J]. West China Medical Journal, 2018, 33(5): 491-498. doi:10.7507/1002-0179.201804027
[2] Zhang XH, Shao SS, Zhao LF, et al. ER stress contributes to high-fat diet-induced decrease of thyroglobulin and hypothyroidism[J]. American Journal of Physiology Endocrinology and Metabolism, 2019, 316(3): 510-518. doi:10.1152/ajpendo.00194.2018
[3] de Sousa MC, Gjorgjieva M, Dolicka D, et al. Deciphering miRNAs' action through miRNA editing[J]. International Journal of Molecular Sciences, 2019, 20(24): 6249. doi:10.3390/ijms20246249
[4] 赵静, 柏力萄, 李菲, 等. MicroRNA在甲状腺功能减退症中的作用[J]. 世界科学技术-中医药现代化, 2019, 21(2): 260-266. doi:10.11842/wst.2019.02.017 ZHAO Jing, BAI Litao, LI Fei, et al. Role of microRNA in hypothyroidism[J]. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology, 2019, 21(2): 260-266. doi:10.11842/wst.2019.02.017
[5] Guedes EC, da Silva IB, Lima VM, et al. High fat diet reduces the expression of miRNA-29b in heart and increases susceptibility of myocardium to ischemia/reperfusion injury[J]. Journal of Cellular Physiology, 2019, 234(6): 9399-9407. doi:10.1002/jcp.27624
[6] Abdollahi M, Kato M, Lanting LD, et al. Role of miR-379 in high-fat diet-induced kidney injury and dysfunction[J]. American Journal of Physiology Renal Physiology, 2022, 323(6): 686-699. doi:10.1152/ajprenal.00213.2022
[7] Sticht C, de La Torre C, Parveen A, et al. miRWalk: an online resource for prediction of microRNA binding sites[J]. PLoS One, 2018, 13(10): e0206239. doi:10.1371/journal.pone.0206239
[8] Zhou YY, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets[J]. Nature Communications, 2019, 10(1): 1523. doi:10.1038/s41467-019-09234-6
[9] Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets[J]. Nucleic Acids Research, 2021, 49(D1): 605-612. doi:10.1093/nar/gkaa1074
[10] Liu YY, Yin ZL, Wang Y, et al. Exploration and validation of key genes associated with early lymph node metastasis in thyroid carcinoma using weighted gene co-expression network analysis and machine learning[J]. Frontiers in Endocrinology, 2023, 14: 1247709. doi:10.3389/fendo.2023.1247709
[11] Chiovato L, Magri F, Carlé A. Hypothyroidism in context: where we've been and where we're going[J]. Advances in Therapy, 2019, 36(Suppl 2): 47-58. doi:10.1007/s12325-019-01080-8
[12] 中国医师协会中西医结合医师分会内分泌与代谢病学专业委员会. 成人原发性甲状腺功能减退症病证结合诊疗指南[J]. 世界中医药, 2023, 18(16): 2265-2272. doi:10.3969/j.issn.1673-7202.2023.16.002
[13] Chaker L, Razvi S, Bensenor IM, et al. Hypothyroidism [J]. Nat Rev Dis Primers, 2022, 8(1): 30. doi:10.1038/s41572-022-00357-7
[14] Benvenga S, Nordio M, Laganà AS, et al. The role of inositol in thyroid physiology and in subclinical hypothyroidism management[J]. Frontiers in Endocrinology, 2021, 12: 662582. doi:10.3389/fendo.2021.662582
[15] Jing L, Zhang Q. Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion[J]. Frontiers in Endocrinology, 2022, 13: 992883. doi:10.3389/fendo.2022.992883
[16] Riesco-eizaguirre G, Santisteban P, de La vieja A. The complex regulation of NIS expression and activity in thyroid and extrathyroidal tissues[J]. Endocrine-Related Cancer, 2021, 28(10): 141-165. doi:10.1530/ERC-21-0217
[17] Kardalas E, Sakkas E, Ruchala M, et al. The role of transforming growth factor beta in thyroid autoimmunity: current knowledge and future perspectives[J]. Reviews in Endocrine & Metabolic Disorders, 2022, 23(3): 431-447. doi:10.1007/s11154-021-09685-7
[18] Fernández-méndez C, Santisteban P. A critical balance between PAX8 and the hippo mediator TAZ determines sodium/iodide symporter expression and function[J]. Thyroid, 2022, 32(3): 315-325. doi:10.1089/thy.2021.0191
[19] Romitti M, Eski SE, Fonseca BF, et al. Single-cell trajectory inference guided enhancement of thyroid maturation in vitro using TGF-beta inhibition[J]. Frontiers in Endocrinology, 2021, 12: 657195. doi:10.3389/fendo.2021.657195
[20] Dong S, Liu QY, Jiang M, et al. Xiao-Luo-Wan treats propylthiouracil-induced goiter with hypothyroidism in rats through the PI3K-AKT/RAS pathways based on UPLC/MS and network pharmacology[J]. Journal of Ethnopharmacology, 2022, 289: 115045. doi:10.1016/j.jep.2022.115045
[21] 康春嵋, 李山, 郭志玲. 基于调控PI3K-AKT通路探讨艾灸关元穴治疗甲状腺功能减退的作用机制[J]. 世界中西医结合杂志, 2021, 16(10): 1831-1835. doi:10.13935/j.cnki.sjzx.211012 KANG Chunmei, LI Shan, GUO Zhiling. Research on the mechanism of moxibustion at Guanyuan acupoint in treating hy-pothyroidism based on regulating PI3 K-AKT pathway[J]. World Journal of Integrated Traditional and Western Medicine, 2021, 16(10): 1831-1835. doi:10.13935/j.cnki.sjzx.211012
[22] Oh JM, Ahn BC. Molecular mechanisms of radioactive iodine refractoriness in differentiated thyroid cancer: impaired sodium iodide symporter(NIS)expression owing to altered signaling pathway activity and intracellular localization of NIS[J]. Theranostics, 2021, 11(13): 6251-6277. doi:10.7150/thno.57689
[23] Russo SC, Salas-lucia F, Bianco AC. Deiodinases and the metabolic code for thyroid hormone action[J]. Endocrinology, 2021, 162(8): bqab059. doi:10.1210/endocr/bqab059
[24] Pelaz SG, Tabenero A. Src: coordinating metabolism in cancer[J]. Oncogene, 2022, 41(45): 4917-4928. doi:10.1038/s41388-022-02487-4
[25] Faria M, Domingues R, Bugalho MJ, et al. Analysis of NIS plasma membrane interactors discloses key regulation by a SRC/RAC1/PAK1/PIP5K/EZRIN pathway with potential implications for radioiodine re-sensitization therapy in thyroid cancer[J]. Cancers, 2021, 13(21): 5460. doi:10.3390/cancers13215460
[26] Rajkumar K, Nichita A, Anoor PK, et al. Understanding perspectives of signalling mechanisms regulating PEBP1 function[J]. Cell Biochemistry and Function, 2016, 34(6): 394-403. doi:10.1002/cbf.3198
[27] Giuliani C, Bucci I, Napolitano G. The role of the transcription factor nuclear factor-kappa B in thyroid autoimmunity and cancer[J]. Frontiers in Endocrinology, 2018, 9: 471. doi:10.3389/fendo.2018.00471
[28] 王芳, 陈华, 商丽红, 等. U0126对子宫内膜异位症大鼠MEK/ERK/NF-κB通路及增殖侵袭的影响[J]. 山东大学学报(医学版), 2021, 59(9): 148-154. doi:10.6040/j.issn.1671-7554.0.2021.0865 WANG Fang, CHEN Hua, SHANG Lihong, et al. Effects of U0126 on MEK/ERK/NF-κB pathway, proliferation and invasion in rats with endometriosis[J]. Journal of Shandong University(Health Sciences), 2021, 59(9): 148-154. doi:10.6040/j.issn.1671-7554.0.2021.0865
[29] Xu HS, Zhang AK, Han XY, et al. ITGB2 as a prognostic indicator and a predictive marker for immunotherapy in gliomas[J]. Cancer Immunology, Immunotherapy, 2022, 71(3): 645-660. doi:10.1007/s00262-021-03022-2
[30] Miko s H, Miko s M, Obara-moszy Ska M, et al. The role of the immune system and cytokines involved in the pathogenesis of autoimmune thyroid disease(AITD)[J]. Endokrynologia Polska, 2014, 65(2): 150-155. doi:10.5603/EP.2014.0021
[31] Tao PF, Han X, Wang QT, et al. A gain-of-function variation in PLCG1 causes a new immune dysregulation disease[J]. Journal of Allergy and Clinical Immunology, 2023, 152(5): 1292-1302. doi:10.1016/j.jaci.2023.06.020
[32] Brivio P, Sbrini G, Corsini G, et al. Chronic restraint stress inhibits the response to a second hit in adult male rats: a role for BDNF signaling[J]. International Journal of Molecular Sciences, 2020, 21(17): 6261. doi:10.3390/ijms21176261
[33] Smith TJ. Insulin-like growth factor pathway and the thyroid[J]. Frontiers in Endocrinology, 2021, 12: 653627. doi:10.3389/fendo.2021.653627
[34] López-márouez A, Carrasco-López C, Fernández-Méndez C, et al. Unraveling the complex interplay between transcription factors and signaling molecules in thyroid differentiation and function, from embryos to adults[J]. Frontiers in Endocrinology, 2021, 12: 654569. doi:10.3389/fendo.2021.654569
[35] 梁伟, 孙禹, 陈丽新, 等. 消瘰丸基于PI3K/Akt/mTORC1通路对实验性甲状腺肿大鼠的干预机制[J]. 中国实验方剂学杂志, 2022, 28(8): 30-36. doi:10.13422/j.cnki.syfjx.20220603 LIANG Wei, SUN Yu, CHEN Lixin, et al. Intervention mechanism of xiaoluowan on experimental goiter rats based on PI3K/Akt/mTORC1 pathway[J]. Chinese Journal of Experimental Traditional Medical Formulae, 2022, 28(8): 30-36. doi:10.13422/j.cnki.syfjx.20220603
[36] Cheng HM, Xing MM, Zhou YP, et al. HSP90β promotes osteoclastogenesis by dual-activation of cholesterol synthesis and NF-κB signaling[J]. Cell Death and Differentiation, 2023, 30(3): 673-686. doi:10.1038/s41418-022-01071-3
[37] Ho PTB, Clark IM, Le LTT. MicroRNA-based diagnosis and therapy[J]. International Journal of Molecular Sciences, 2022, 23(13): 7167. doi:10.3390/ijms23137167
[1] 王惟一,时蕾,张志玉,张贵玲,时光刚. 高脂饮食对过敏性鼻炎小鼠致敏影响和肠道菌群改变的研究[J]. 山东大学耳鼻喉眼学报, 2023, 37(3): 21-29.
[2] 李超友,王安洋，薛刚. 中心型肥胖与头颈癌的关系[J]. 山东大学耳鼻喉眼学报, 2022, 36(2): 120-125.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
[1] 万俐佳,鲁海涛,姜义道,刘 辉,李 琴,佘腊枝 . 改良腭咽成形术治疗阻塞性睡眠呼吸暂停综合征41例[J]. 山东大学耳鼻喉眼学报, 2008, 22(3): 204 -205 .
[2] 于青青 ,王跃建 . 硬质耳内镜的临床应用进展[J]. 山东大学耳鼻喉眼学报, 2008, 22(3): 222 -224 .
[3] 吉晓滨,邓家德,臧林泉,王 磊,谢 军 . 豚鼠变应性鼻炎模型血清组胺的测定[J]. 山东大学耳鼻喉眼学报, 2008, 22(3): 228 -230 .
[4] 向登,卢永田,孙焕吉 . 鼻内镜下修补脑脊液鼻漏19例并文献复习[J]. 山东大学耳鼻喉眼学报, 2008, 22(3): 234 -236 .
[5] 殷国华,钟 笑 . 激光减容术治疗舌扁桃体肥大的远期疗效[J]. 山东大学耳鼻喉眼学报, 2008, 22(3): 280 -282 .
[6] 刘联合 . 刎颈伤21例[J]. 山东大学耳鼻喉眼学报, 2008, 22(3): 283 -284 .
[7] 蔡 谦,苏振忠,文卫平,柴丽萍,叶 辉,滕以书,吴 旋 . 成人打鼾与口咽腔狭窄评分的相关性[J]. 山东大学耳鼻喉眼学报, 2008, 22(4): 289 -292 .
[8] 储九圣,黄永久,鲍学礼,田为中 . 甲状舌管癌1例并文献复习[J]. 山东大学耳鼻喉眼学报, 2008, 22(4): 322 -324 .
[9] 张吉仲,李大建 . 鼻内镜下鼻中隔软骨或筛骨修补鼻中隔穿孔[J]. 山东大学耳鼻喉眼学报, 2008, 22(4): 336 -337 .
[10] 张端和,陈建平,马政旺,王 成,王护国 . 游离、旋转全层皮瓣移植治疗鼻、面部皮肤缺损[J]. 山东大学耳鼻喉眼学报, 2008, 22(4): 338 -339 .
网站版权所有 © 2018 《山东大学耳鼻喉眼学报》编辑部　
地址：山东省济南市山大南路27号（250100）电话：+86-0531-88366912 E-mail: ebhxb@sdu.edu.cn
本系统由北京玛格泰克科技发展有限公司设计开发