Please wait a minute...
浙江大学学报（医学版）
J Zhejiang Univ (Med Sci)  2018, Vol. 47 Issue (2): 187-193    DOI: 10.3785/j.issn.1008-9292.2018.04.13
    
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
Download: HTML( 15 )   PDF(1277KB)
Export: BibTeX | EndNote (RIS)      

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     
Received: 26 January 2018      Published: 24 July 2018
CLC:  R736.1  
Corresponding Authors: HUANG Ping     E-mail: panzf@zjcc.org.cn;huangping1841@zjcc.org.cn
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
PAN Zongfu
FANG Qilu
ZHANG Yiwen
LI Li
HUANG Ping
Cite this article:

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.

URL:

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


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

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 
Fig 1 Identification and hierarchical clustering analysis of differentially expressed genes between anaplastic thyroid carcinoma and normal thyroid tissues
Fig 2 GO (Biological Process) terms and KEGG pathways enrichment of differentially expressed genes between anaplastic thyroid carcinoma and normal thyroid tissues
Fig 3 The protein-protein interaction network of differentially expressed genes between anaplastic thyroid carcinoma and normal thyroid tissues
Fig 4 Module analysis of protein-protein interaction network and gene function annotation
Fig 5 Drugs repurposing for anaplastic thyroid carcinoma and chemical structure similarity analysis
[1]   SIEGEL R L , MILLER K D , JEMAL A . Cancer statistics, 2017[J]. CA Cancer J Clin, 2017, 67 (1): 7- 30
doi: 10.3322/caac.21387
[2]   CHEN W , ZHENG R , BAADE P D et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66 (2): 115- 132
doi: 10.3322/caac.21338
[3]   FAGIN J A , WELLS S A . Biologic and clinical perspectives on thyroid cancer[J]. N Engl J Med, 2016, 375 (11): 1054- 1067
doi: 10.1056/NEJMra1501993
[4]   WISEMAN S M , MASOUDI H , NIBLOCK P et al. Anaplastic thyroid carcinoma:expression profile of targets for therapy offers new insights for disease treatment[J]. Ann Surg Oncol, 2007, 14 (2): 719- 729
doi: 10.1245/s10434-006-9178-6
[5]   LANDA I , IBRAHIMPASIC T , BOUCAI L et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers[J]. J Clin Invest, 2016, 126 (3): 1052- 1066
doi: 10.1172/JCI85271
[6]   SANTARPIA L , EL-NAGGAR A K , COTEG J et al. Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer[J]. J Clin Endocrinol Metab, 2008, 93 (1): 278- 284
doi: 10.1210/jc.2007-1076
[7]   LANDA I , GANLY I , CHANT A et al. Frequent somatic TERT promoter mutations in thyroid cancer:higher prevalence in advanced forms of the disease[J]. J Clin Endocrinol Metab, 2013, 98 (9): E1562- E1566
doi: 10.1210/jc.2013-2383
[8]   HOU P , LIU D , SHAN Y et al. Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer[J]. Clin Cancer Res, 2007, 13 (4): 1161- 1170
doi: 10.1158/1078-0432.CCR-06-1125
[9]   HUSAIN A , HU N , SADOW P M et al. Expression of angiogenic switch, cachexia and inflammation factors at the crossroad in undifferentiated thyroid carcinoma with BRAF(V600E)[J]. Cancer Lett, 2016, 380 (2): 577- 585
doi: 10.1016/j.canlet.2015.07.012
[10]   EJLERTSEN B , TUXEN M K , JAKOBSEN E H et al. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer:DBCG 07-READ, an open-label, phase Ⅲ, randomized trial[J]. J Clin Oncol, 2017, 35 (23): 2639- 2646
doi: 10.1200/JCO.2017.72.3494
[11]   TURNER J G , DAWSON J L , GRANT S et al. Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase Ⅱ inhibitors[J]. J Hematol Oncol, 2016, 9 (1): 73
doi: 10.1186/s13045-016-0304-z
[12]   TARPGAARD L S , QVORTRUP C , NYGRD S B et al. A phase Ⅱ study of epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification[J]. BMC Cancer, 2016, 16 91
doi: 10.1186/s12885-016-2124-5
[13]   CHRISTNER P J , AYITEY S . Extracellular matrix containing mutated fibrillin-1(Fbn1) down regulates Col1a1, Col1a2, Col3a1, Col5a1, and Col5a2 mRNA levels in Tsk/+ and Tsk/Tsk embryonic fibroblasts[J]. Amino Acids, 2006, 30 (4): 445- 451
doi: 10.1007/s00726-005-0265-y
[14]   BARCUS C E , O'LEARY K A , BROCKMAN J L et al. Elevated collagen-Ⅰ augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells[J]. Breast Cancer Res, 2017, 19 (1): 9
doi: 10.1186/s13058-017-0801-1
[15]   CHEN L , MIN L , WANG X et al. Loss of RACK1 promotes metastasis of gastric cancer by inducing a miR-302c/IL8 signaling loop[J]. Cancer Res, 2015, 75 (18): 3832- 3841
doi: 10.1158/0008-5472.CAN-14-3690
[16]   SANMAMED M F , CARRANZA-RUA O , ALFARO C et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins[J]. Clin Cancer Res, 2014, 20 (22): 5697- 5707
doi: 10.1158/1078-0432.CCR-13-3203
[1] MI Shuang,WU Yanjun,HONG Zhenghua,WANG Zhangfu,FENG Xingbing,ZHENG Guangbin. Expression of TLR4/MyD88/NF-κB pathway genes and its related inflammatory factors in secondary spinal cord injury[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 609-616.
[2] LIU Jingwen,YANG Xinglian,SHEN Kaili,ZENG Linghui,SUN Yan. Chloroxoquinoline inhibits invasion in breast cancer via down-regulating Rho/Rho kinase signaling pathway[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 631-637.
[3] PAN Zongfu,HU Xiaoping,ZHANG Yiwen,LI Li,HUANG Ping. Identification of dynamic co-expression networks in peripheral blood of rats after middle cerebral artery occlusion[J]. J Zhejiang Univ (Med Sci), 2019, 48(6): 587-593.
[4] ZHU Ziling, TAN Jing, DENG Hong. Nucleus translocation of membrane/cytoplasm proteins in tumor cells[J]. J Zhejiang Univ (Med Sci), 2019, 48(3): 318-325.
[5] WANG Qingmei, XU Qianzi, WEI Anyi, CHEN Shishuo, ZHANG Chong, ZENG Linghui. High dose vitamin C inhibits proliferation of breast cancer cells through reducing glycolysis and protein synthesis[J]. J Zhejiang Univ (Med Sci), 2019, 48(3): 296-302.
[6] LUN Yongzhi,SUN Jie. Identification of differentially expressed genes in peripheral blood mononuclear cells of patients with hepatocellular carcinoma and its regulatory network analysis[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 148-157.
[7] YANG Kun,HU Xiaosheng. Research progress on miR-21 in heart diseases[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 214-218.
[8] SHAO Jiale,LI Zhizhong,ZHOU Jian,LI Kai,QIN Rong,CHEN Keming. Effect of low-frequency pulsed electromagnetic fields on activity of rat calvarial osteoblasts through IGF-1R/NO signaling pathway[J]. J Zhejiang Univ (Med Sci), 2019, 48(2): 158-164.
[9] TANG Siyang,YE Jia,LI Yuezhou. I1363T mutation induces the defects in fast inactivation of human skeletal muscle voltage-gated sodium channel[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 12-18.
[10] SUN Boqiang,WANG Qiongyan,PAN Dongli. Mechanisms of herpes simplex virus latency and reactivation[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 89-101.
[11] DU Dongfen,ZHU Lixia,WANG Yungui,YE XiujinG. Expression of WT1 gene and its prognostic value in patients with acute myeloid leukemia[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 50-57.
[12] YE Peiwu,YU Xiafei,MA Cheng,YANG Wei. Extraction and purification of NUDT9 homology domain of human transient receptor potential melastatin 2 channel[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 5-11.
[13] LI Chuntao,ZHANG Huibing,ZHANG Yan. Single-particle cryo-electron microscopy opens new avenues in structural biology of G protein-coupled receptor[J]. J Zhejiang Univ (Med Sci), 2019, 48(1): 39-43.
[14] SHI Ting,YE Xiujin. Roles of CCAAT enhancer binding protein α in acute myeloblastic leukemia[J]. J Zhejiang Univ (Med Sci), 2018, 47(5): 552-557.
[15] ZHU Feng,FAN Miao,XU Ziwei,CAI Yiting,CHEN Yizhen,YU Shuang,ZENG Linghui. Neuroprotective effect of rapamycin against Parkinson's disease in mice[J]. J Zhejiang Univ (Med Sci), 2018, 47(5): 465-472.