TCDD对胶质母细胞瘤中环氧合酶2基因表达的影响和生物学作用  

Effect of TCDD on Expression of Cyclooxygenase-2 Gene and Its Biological Role in Glioblastoma

作　　者：彭颖蓓 陈旸升 刘奕耘 李云平 徐丽[1] 谢群慧[1] 赵斌[1,2,4] Peng Yingbei;Chen Yangsheng;Liu Yiyun;Li Yunping;Xu Li;Xie Qunhui;Zhao Bin(State Key Laboratory of Environmental Chemistry and Ecotoxicology,Research Center for Eco-Environmental Sciences,Chinese Academy of Sciences,Beijing 100085,China;College of Resources and Environment,University of Chinese Academy of Sciences,Beijing 100049,China;College of Public Health,Chongqing Medical University,Chongqing 400030,China;School of Environment,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China)

机构地区：[1]中国科学院生态环境研究中心,环境化学与生态毒理学国家重点实验室,北京100085 [2]中国科学院大学资源与环境学院,北京100049 [3]重庆医科大学公共卫生学院,重庆400030 [4]国科大杭州高等研究院环境学院,杭州310024

出　　处：《生态毒理学报》2023年第4期241-252,共12页Asian Journal of Ecotoxicology

基　　金：国家自然科学基金青年项目(22206202);国家自然科学基金重点项目(21836004);国家重点研发计划项目(2018YFA0901100)。

摘　　要：胶质母细胞瘤(glioblastoma,GBM)是最常见的恶性脑肿瘤,其复发率和死亡率居高不下。环氧合酶2(cyclooxygenase 2,COX2)在正常生理条件下几乎不表达,但持续高表达的COX2常见于各种恶性肿瘤和癌前状态,并参与诸多肿瘤发生发展过程,如血管生成、免疫抑制、迁移侵袭以及化疗抵抗等。二噁英类污染物作为一级致癌物,但目前有关二噁英对GBM发展的研究十分有限。本研究旨在探究二噁英暴露影响GBM发展的分子机制。以COX2为标志物,明确二噁英类污染物中毒性最强的2,3,7,8-二苯并-p-二噁英(2,3,7,8-tetrachlorodibenzo-p-dioxin,TCDD)对胶质母细胞瘤U87细胞中COX2基因表达的影响以及芳香烃受体(aryl hydrocarbon receptor,AhR)在之中的作用,并借助转录组测序进一步探究TCDD暴露后U87细胞中COX2参与的生物过程。实验结果显示,TCDD以AhR依赖的方式上调U87细胞中COX2基因表达并具有时间-剂量依赖效应。转录组分析结果表明,TCDD暴露显著改变了U87细胞中细胞黏附、胞外刺激检测以及膜转运等相关通路的基因表达,COX2可能通过影响脂质形成和维持炎症反应参与U87的改变。进一步的互作分析发现COX2基因与IL1B和CYP2E1相关。本研究补充了TCDD在U87细胞中上调COX2表达的可能机制和影响,并为今后对二噁英促癌作用的研究提供参考。Glioblastoma(GBM)is the most common malignant brain tumor which has high recurrence and mortality rate.Cyclooxygenase 2(COX2)is not expressed under normal physiological conditions,but the continuously high expression of COX2 is common in various malignant tumors and precancerous states.COX2 is involved in many tumors’physiological activities,such as angiogenesis,immunosuppression,migration invasion,and chemotherapy resistance.As primary carcinogen,the research about dioxin on glioblastoma occurrence and development is very limited.This study is aimed to investigate the effect and mechanism of dioxin on the expression of COX2 gene and its subsequent effects on glioblastoma.We investigated the effect of dioxin on COX2 gene expression in glioblastoma U87 cells and the role of aryl hydrocarbon receptor(AhR).Through in vitro cell experiments,the most toxic dioxin,2,3,7,8-dibenzo-p-dioxin(TCDD),was used as a representative pollutant to explore whether dioxin can change the expression of COX2 gene through the classical AhR pathway in U87 cell.Finally,transcriptome sequencing was used to further explore the biological role of COX2 in U87 cells after TCDD treatment.The experimental results showed that TCDD could upregulate the expression of COX2 gene in U87 cells in an AhR-dependent manner and had significant time-dependent and dose-dependent effects.The results of transcriptome analysis showed that TCDD exposure significantly altered cell adhesion,extracellular stimulation detection,and membrane transport pathways in U87 cells,and COX2 perhaps participate in the change of U87 by affecting lipid formation and maintaining inflammatory response.Through further interaction analysis,we found that COX2 gene was associated with IL1B and CYP2E1.This study supplements the possible mechanism and influence of TCDD upregulating COX2 expression in U87 cells,and provides more details for future researches on the cancer promoting effect of dioxins.

关 键 词：二噁英 胶质母细胞瘤U87细胞 环氧合酶2(COX2) 转录组分析 芳香烃受体 

分 类 号：X171.5[环境科学与工程—环境科学]