利用网络分析预测As_2O_3治疗结直肠癌的靶基因
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摘要
目的:探究三氧化二砷(arsenic trioxide,As_2O_3)作用于结直肠癌的靶基因。方法:利用pharm GKB数据库和drugbank5. 0数据库分别提取三氧化二砷的直接靶基因,利用STRING10. 5数据库筛选与三氧化二砷已知靶基因互相作用的蛋白,利用web Gestalt数据库对互作蛋白进行通路分析和GO注释,运用c Bio Protal数据库和The Human Protein Atlas数据库对重点通路的核心基因进行变异和表达分析。结果:pharm GKB数据库和drugbank5. 0数据库共提取出11个直接靶基因,STRING10. 5数据库筛选出384个互作蛋白,web Gestalt数据库的GO注释这384个靶基因主要集中于19类分子功能,在前10条通路中筛选出3条与结直肠癌有关的通路,3个核心基因在结直肠癌中存在点突变和基因缺失,其中NF-κB1和RELA在结直肠癌组织中存在高表达。结论:三氧化二砷可能通过NF-κB信号通路治疗结直肠癌。
Objective: To explore the target genes of As_2O_3 in therapy of colorectal cancer( CRC). Methods: The direct target genes were extracted by pharm GKB database and drugbank5. 0 database. Direct protein targets associated genes were filtrated by STRING10. 5 database. KEGG pathway and GO analysis of interactive protein were operated by web Gestalt database. Hub genes from important pathways were analyzed by c Bio Protal database and the Human Protein Atlas database. Results: 11 direct target genes were found from pharm GKB and drugbank5. 0. 384 direct protein targets associated genes were identified for As_2O_3 by STRING10. 5. And 19 molecular functions and top 10 pathways were explored by web Gestalt. Finally,3 hub genes were found out. Moreover,3 hub genes have mutation and gene deep deletion in CRC,of which NF-κB1 and RELA are highly expressed in CRC tissues. Conclusion: As_2O_3 may be used to treat CRC through the NF-κB signaling pathway.
Objective: To explore the target genes of As_2O_3 in therapy of colorectal cancer( CRC). Methods: The direct target genes were extracted by pharm GKB database and drugbank5. 0 database. Direct protein targets associated genes were filtrated by STRING10. 5 database. KEGG pathway and GO analysis of interactive protein were operated by web Gestalt database. Hub genes from important pathways were analyzed by c Bio Protal database and the Human Protein Atlas database. Results: 11 direct target genes were found from pharm GKB and drugbank5. 0. 384 direct protein targets associated genes were identified for As_2O_3 by STRING10. 5. And 19 molecular functions and top 10 pathways were explored by web Gestalt. Finally,3 hub genes were found out. Moreover,3 hub genes have mutation and gene deep deletion in CRC,of which NF-κB1 and RELA are highly expressed in CRC tissues. Conclusion: As_2O_3 may be used to treat CRC through the NF-κB signaling pathway.
引文
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[2]Swindell EP,Hankins PL,Chen H,et al. Anticancer activity of small-molecule and nanoparticulate arsenic(III)complexes[J].Inorganic Chemistry,2013,52(21):12292-12304.
[3]Keyhani M. Use of arsenic trioxide as a first-line single agent in the treatment of acute promyelocytic leukemia[J]. Journal of Clinical Oncology,2012,30(2):217.
[4]Lee JC,Lee HY,Chang HM,et al. Arsenic trioxide as a vascular disrupting agent:Synergistic effect with irinotecan on tumor growth delay in a CT26 allograft model[J]. Translational Oncology,2013,6(1):83-91.
[5]Wang X,Jiang F,Mu J,et al. Arsenic trioxide attenuates the invasion potential of human liver cancer cells through the demethylation-activated microRNA-491[J]. Toxicology Letters,2014,227(2):75.
[6]Whirl-Carrillo M,Mcdonagh EM,Hebert JM,et al. Pharmacogenomics knowledge for personalized medicine[J]. Clinical Pharmacology&Therapeutics,2012,92(4):414-417.
[7]Wishart DS,Feunang YD,Guo AC,et al. Drug bank 5. 0:A major update to the drugbank database for 2018[J]. Nucleic Acids Research,2017,46(Database issue):D1074-D1082.
[8]Szklarczyk D,Morris JH,Cook H,et al. The STRING database in2017:Quality-controlled protein-protein association networks,made broadly accessible[J]. Nucleic Acids Research,2017,45(Database issue):D362-D368.
[9]Wang J,Duncan D,Shi Z,et al. WEB-based gene set analysis toolkit(WebGestalt):Update 2013[J]. Nucleic Acids Research,2013,41(Web Server issue):W77.
[10]Gao J,Aksoy BA,Dogrusoz U,et al. Integrative analysis of complex cancer genomics and clinical profiles using the cbioportal[J]. Science Signaling,2013,6(269):pl1.
[11]Uhlen M,Zhang C,Lee S,et al. A pathology atlas of the human cancer transcriptome[J]. Science,2017,357(6352). doi:10.1126/science. aan2507.
[12]Eyvani H,Moghaddaskho F,Kabuli M,et al. Arsenic trioxide induces cell cycle arrest and alters DNA methylation patterns of cell cycle regulatory genes in colorectal cancer cells[J]. Life Sciences,2016,167:67-77.
[13]Feng T,Xu J,He P,et al. Decrease in stathmin expression by arsenic trioxide inhibits the proliferation and invasion of osteosarcoma cells via the MAPK signal pathway[J]. Oncology Letters,2017,14(2):1333-1340.
[14]Subbarayan PR,Lee K,Ardalan B. Arsenic trioxide suppresses thymidylate synthase in 5-FU-resistant colorectal cancer cell line HT29 in vitro re-sensitizing cells to 5-FU[J]. Anticancer Research,2010,30(4):1157.
[15]Bakhshaiesh TO,Armat M,Shanehbandi D,et al. Arsenic trioxide promotes paclitaxel cytotoxicity in resistant breast cancer cells[J]. Asian Pacific Journal of Cancer Prevention Apjcp,2015,16(13):5191-5197.
[16]Yao Yazhou,Li Xiaoni,Zheng Yinsuo. Clinical analysis of As2O3and low dose Homoharringtonine-cytarabine in the treatment of45 patients with refractory or relapsed non-M3 acute non-lymphocytic leukemia[J]. Modern Oncology,2015,23(20):3030-3032.[姚亚洲,李小妮,郑引索.含三氧化二砷方案治疗复发难治性非M3急性非淋巴细胞白血病45例疗效观察[J].现代肿瘤医学,2015,23(20):3030-3032.]
[17]Ge LW,Xie WF,Gu JH,et al. Expression level of HIF-1αand GLS2 in the colorectal cancer tissue and its clinical significance[J]. Chinese Journal of Operative Procedures of General Surgery(Electronic Version),2017,11(3):265-268.[葛丽卫,谢伟峰,顾金华,等.结直肠癌患者组织中HIF-1α和GLS2表达水平与病理程度和预后的相关性[J].中华普外科手术学杂志:电子版,2017,11(3):265-268.]
[18]Hayden MS,Ghosh S. Shared principles in NF-kappaB signaling[J]. Cell,2008,132(3):344-362.
[19]Gupta SC,Sundaram C,Reuter S,et al. Inhibiting NF-κB activation by small molecules as a therapeutic strategy[J]. Biochimica et Biophysica Acta,2010,1799(10-12):775.
[20]Budhu S,Wolchok J,Merghoub T. The importance of animal models in tumor immunity and immunotherapy[J]. Current Opinion in Genetics&Development,2014,24(4):46-51.