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浙江大学学报（医学版）
浙江大学学报（医学版）  2018, Vol. 47 Issue (2): 187-193    DOI: 10.3785/j.issn.1008-9292.2018.04.13
原著     
基于生物信息学的未分化甲状腺癌关键发病机制及其潜在干预靶点研究
潘宗富1(),方琦璐1,张轶雯1,李莉2,黄萍1,*()
1. 浙江省肿瘤医院药剂科, 浙江 杭州 310022
2. 浙江省淳安县第一人民医院药剂科, 浙江 杭州 311700
Identification of key pathways and drug repurposing for anaplastic thyroid carcinoma by integrated bioinformatics analysis
PAN Zongfu1(),FANG Qilu1,ZHANG Yiwen1,LI Li2,HUANG Ping1,*()
1. Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou 310022, China
2. Department of Pharmacy, First People's Hospital of Chun'an, Hangzhou 311700, China
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摘要：

目的: 阐明未分化型甲状腺癌（ATC）的分子病理状态，并挖掘其潜在的干预策略。方法: 利用GEO数据库联合R语言分析ATC组织与正常甲状腺组织差异表达的基因；利用京都基因与基因组百科全书（KEGG）通路数据库和基因本体（GO）数据库对差异表达的基因进行富集和功能注释；基于STRING数据库及Cytoscape软件构建蛋白质相互作用网络，分析其关键网络节点和基因簇；最后采用L1000CDS2数据库预测ATC的潜在治疗药物。结果: 共获得2087个差异表达基因。与正常甲状腺组织相比，ATC组织细胞内信号通路及肿瘤微环境均发生显著改变，包括PI3K-Akt信号的持续激活、p53通路的激活、炎症反应、细胞外基质重塑等。蛋白质相互作用网络提示存在3个重要的基因簇和9个关键节点。将差异表达基因与L1000CDS2数据库进行比对后发现22个能够逆转ATC病理状态的潜在化合物。结论: 本研究揭示了ATC发病机制中的关键节点，为ATC的治疗提供了潜在的靶点。
关键词： 甲状腺肿瘤/病理生理学;  计算生物学;  基因表达;  信号传导;  蛋白质类;  基因调控网络    
Abstract:

Objective: To identify hub genes and key pathways associated with anaplastic thyroid carcinoma (ATC), and to explore possible intervention strategy. Methods: The differentially expressed genes (DEGs) in ATC were identified by Gene Expression Omnibus (GEO) combined with using R language; the pathway enrichment of DEGs were performed by using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The protein-protein interaction (PPI) network of DEGs was constructed by STRING database and visualized by Cytoscape. Furthermore, the hub genes and key nodes were calculated by MCODE. Finally, the drug repurposing was performed by L1000CDS2. Results: A total of 2087 DEGs were identified. The DEGs were clustered based on functions and pathways with significant enrichment analysis, among which PI3K-Akt signaling pathway, p53 signaling pathway, inflammatory response, extracellular matrix organization were significantly upregulated. The PPI network was constructed and the most significant three modules and nine genes were filtered. Twenty-two potential compounds were repurposed for ATC treatment. Conclusion: Using integrated bioinformatics analysis, we have identified hub genes and key pathways in ATC, and provide novel strategy for the treatment of ATC.
Key words: Thyroid neoplasms/physiopathology    Computational biology    Gene expression    Signal transduction    Proteins    Gene regulatory networks
收稿日期: 2018-01-26 出版日期: 2018-07-24
:  R736.1  
基金资助: 浙江省基础公益研究计划(LQ18H160017);浙江省医药卫生科技计划(2017192848, 2018245206);杭州市卫生科技计划(2017B56)
通讯作者: 黄萍     E-mail: panzf@zjcc.org.cn;huangping1841@zjcc.org.cn
作者简介: 潘宗富(1989-), 男, 博士, 药师, 主要从事内分泌肿瘤发病机制研究; E-mail:panzf@zjcc.org.cn; https://orcid.org/0000-0002-4054-6660
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引用本文:

潘宗富,方琦璐,张轶雯,李莉,黄萍. 基于生物信息学的未分化甲状腺癌关键发病机制及其潜在干预靶点研究[J]. 浙江大学学报（医学版）, 2018, 47(2): 187-193.

PAN Zongfu,FANG Qilu,ZHANG Yiwen,LI Li,HUANG Ping. Identification of key pathways and drug repurposing for anaplastic thyroid carcinoma by integrated bioinformatics analysis. J Zhejiang Univ (Med Sci), 2018, 47(2): 187-193.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2018.04.13    或    http://www.zjujournals.com/med/CN/Y2018/V47/I2/187

图 1  未分化型甲状腺癌组织与正常甲状腺组织差异表达基因热图和聚类分析结果
图 2  未分化型甲状腺癌组织与正常甲状腺组织差异表达基因GO、KEGG富集和注释结果
图 3  未分化型甲状腺癌组织与正常甲状腺组织差异表达基因的蛋白质相互作用网络
图 4  蛋白质相互作用网络关键基因簇分析及其功能注释
图 5  基于差异表达基因和L1000CDS2数据库预测的未分化型甲状腺癌干预药物及聚类
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