基于基因表达谱的途径筛选肺腺癌治疗药物

中国临床药理学与治疗学 ›› 2010, Vol. 15 ›› Issue (3): 266-271.

基于基因表达谱的途径筛选肺腺癌治疗药物

王桂平^1,2, 叶云^1,3, 杨晓勤¹, 陈新美¹, 梁爽¹, 郑文岭¹, 马文丽¹

¹南方医科大学基因工程研究所, 广州510515, 广东;
²广州医学院护理学院,广州510180, 广东;
³广西工学院生物与化学工程系, 柳州545006, 广西

收稿日期:2010-01-11 修回日期:2010-01-11 发布日期:2020-10-14
作者简介:王桂平, 男, 博士, 研究方向:生物信息学与肿瘤治疗药物研究。E-mail:docgpwang@yahoo.com.cn

Gene expression profiles-based approach identifies candidate therapeutic compounds for lung adenocarcinoma

WANG Gui-ping^1,2, YE Yun^1,3, YANG Xiao-qing¹, CHEN Xin-mei¹, LIA NG Shuang¹, ZHENG Wen-ling¹, MA Wen-li¹

¹Institute of Genetic Engineering, Southern Medical University, Guangzhou 510515, Guangdong, China;
²GuangZhou Medical College, Guangzhou 510180, Guangdong, China;
³Department of Biological and Chemical Engineering, Guangxi University of Technology, Liuzhou 545006,Guangxi,China

Received:2010-01-11 Revised:2010-01-11 Published:2020-10-14

摘要/Abstract

摘要： 目的: 探讨基于基因表达谱的途径在肺腺癌治疗药物筛选中的应用。方法: 从GEO 数据库中获得GSE10072 和GSE7670 两个数据集, 然后利用dchip 软件进行差异表达基因分析, 采用基因集富集方法(gene set enrichment analysis,GSEA)对肺腺癌进行通路富集分析, 最后通过Co nnect ivity map(Cmap)筛选肺腺癌候选治疗化合物, 并进行实验验证。结果: 共获得差异表达基379 个, 其中上调基因94 个, 下调基因285 个;GSEA 主要富集到细胞周期等18 条信号通路与肺腺癌相关;通过Cmap 分析, 筛选到V orino stat、15-delta pro staglandin J2、t richo statin A、tanespimy cin 等8 种候选药物或化合物, 在进一步的实验中也证实15d-PGJ (2)可有效抑制A549 细胞的增殖。结论: 基于基因表达谱的途径为药物发现提供新思路, 加速了药物发现过程。

关键词: 基因表达谱, 肺腺癌, Connectivi ty map

Abstract: AIM: To screen the candidate therapeutic compounds for lung adeno carcinoma with gene expression profiles-based approach. METHODS: Two published microarray data (GSE7670 and GSE10072) were downloaded from Gene Expression Omnibus(GEO)web. A meta-analysis were performed with the dchips of tware, and pathway enrichment analysis was done with gene set enrichment analysis method (GSEA).Finally, candidate therapeutic compounds for lung adenocarcinoma were screened by Connectivity map analysis. RESULTS: The rewere 379 differential gene expression, including 94 up-regulated gene and 285 down-regulated gene. Pathway enrichment analy sis showed that there were 18 biological pathw aysrelated with lung adenocarcinoma. With Connectivity map analysis, We screened out eight candida te compounds, including Vorinostat, 15-delta prostaglandin J2, trichostatin A, tanespimycin, etc. In the following experiment, we demo nst rated that 15-delta prostaglandin J2 can inhibit A549 cell prolification. CONCLUSION: Our results demonstrated that gene expression profiles-based approach is perspective for screening the candidate the rapeutic compounds, which accelerates the introduction of compounds into the clinic.

Key words: Gene expression profiles, Lung adenocarcinoma, Connectivity map

中图分类号:

R965.2

王桂平, 叶云, 杨晓勤, 陈新美, 梁爽, 郑文岭, 马文丽. 基于基因表达谱的途径筛选肺腺癌治疗药物[J]. 中国临床药理学与治疗学, 2010, 15(3): 266-271.

WANG Gui-ping, YE Yun, YANG Xiao-qing, CHEN Xin-mei, LIA NG Shuang, ZHENG Wen-ling, MA Wen-li. Gene expression profiles-based approach identifies candidate therapeutic compounds for lung adenocarcinoma[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(3): 266-271.

参考文献

[1] 杨玲, 李连弟, 陈育德, 等.中国肺癌死亡趋势分析及发病、死亡的估计与预测[J].中国肺癌杂志,2005, 8(4):274-278.
[2] Marino P, Pampallona S, Prea to ni A, et al.Chemo the rapyvs suppo rtive care in advanced non-smallcell lung cancer Results of a meta-analy sis of the liter ature[J].Chest, 1994, 106(3):861-865.
[3] Soon YY, Stockle r MR, Askie LM, et al.Duration of chemo thera py for adv anced no n-small-cell lung cancer:a sy stema tic rev iew and me ta-analy sis of randomized trials[J].J Clin Oncol, 2009, 27(20):3277-3283.
[4] Di Maio M, Chiodini P, Geo rgo ulias V, et al.Meta-analy sis of sing le-agent chemo the rapy compared with combinatio n chemo therapy as second-line treatment of advanced non-small-cell lung cancer[J].J Clin Oncol, 2009, 27(11):1836-1843.
[5] Sandler AB, Nemunaitis J, Denham C, et al.Phase I II trial of gemcitabine plus cisplatin versus cisplatin a lone in pa tients with locally advanced or me tasta ticno n-small-cell lung cancer[J].J Clin Onco l, 2000,18(1):122-130.
[6] La rsen JE, Pavey S J, Passmore LH, et al.Expres-sion profiling defines a recurrence sig na ture in lung squamous cell carcinoma[J].Carcinog enesis, 2007,28(3):760-766.
[7] Talbot SG, Estilo C, Maghami E, et al.Gene expressionpro filing allows distinction betw ee n primary and metastatic squamous cell car cinomas in the lung.[J].Cancer Res, 2005, 65(8):3063-3071.
[8] Glinsky GV, Glinskii AB, Stephe nson AJ, et al.Gene expressio n pr ofiling predicts clinical outcome of pr ostate cancer[J].J Clin Invest, 2004, 113(6): 913-923.
[9] Kor rat A, Greiner T, M aurer M, et al.Gene sig nature-based prediction of tumo r respo nse to cy clopho sphamide[J].Cancer Genomics Pro teomics,2007, 4(3):187-195.
[10] Gullans SR.Co nnecting the do ts using g ene-ex pression profiles[J].N Engl J Med, 2006, 355(19):2042-2044.
[11] Lamb J, Cr awfo rd ED, Peck D, et al.The Co nnectivity Map:using gene-expressio n signatures to co nnect small mo lecules, g ene s, and disea se[J].Science, 2006, 313(5795):1929-1935.
[12] Vilar E, Mukher jee B, Kuick R, et al.Gene expression pa tte rns in misma tch repair-deficient colorectal cancer s highlight the po tential the rapeutic ro leof inhibito rs o f the phospha tidy lino sitol 3-kina se-AKT-mammalia n ta rge t o f rapamy cin pa thw ay[J].Clin Cancer Res, 2009, 15(8):2829-2839.
[13] H iero nymus H, Lamb J, Ross KN, et al.Gene expression sig nature-ba sed chemical genomic predictionn identifies a novel class o f HSP90 pathway modulato rs[J].Cancer Cell, 2006, 10(4):321-330.
[14] Zhao Y, Simon R.BRB-Ar rayToo ls Data Archive for H uman Cancer Gene Expressio n:A Unique and Efficient Data Sharing Re so ur ce[J].Cancer I nfo rm,2008, 6:9-15.
[15] Gao G, Jiang J, Liang X, et al.A me ta-analy sis of platinum plus gemcitabine or vino relbine in the treatment of advanced non-small-cell lung cancer[J].Lung Cancer, 2009, 65(3):339-344.
[16] Niels R, Rolf M M, Ralf B, et al.Signal tra nsduction pathways as no vel ther apy targ ets in lung ca ncer[J].Lung Cance r (Am ste rdam, Netherlands),2004, 45(Suppl 2):S177-S186.
[17] Ebi H, Tomida S, Takeuchi T, et al.Relationship of dereg ulated sig naling co nv erg ing ontom TOR with prognosis and classificatio n of lung adeno ca rcinoma show n by tw o independent in silico a naly ses[J].Cancer Res, 2009, 69(9):4027-4035.
[18] Plat ta CS, Greenblatt DY, Kunnimalaiyaan M, et al.The H DAC inhibitor tricho sta tin A inhibitsg rowth of sma ll cell lung cancer cells[J].J Surg Re s, 2007, 142(2):219-226.
[19] Tray no r AM, DubeyS, Eickhoff JC, et al.Vorinostat (NSC # 701852) in pa tients with relapsed non-small ce ll lung cance r:a Wisconsin Oncology Network phase II study[J].J Tho rac Oncol, 2009,4(4):522-526.
[20] 杨敏, 刘昭前.过氧化物酶体增殖物活化受体δ及其在代谢综合征中的作用[J].中国临床药理学与治疗学, 2007, 12(11):1205-1210.