Reactive oxygen species in Ni(II) carcinogenesis

Ni(II) 致癌过程中的活性氧

• 批准号: 8233453
• 负责人: Xianglin Shi
• 金额: $ 32.31万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233453
• 关键词: Animal Experiments; Animals; Antioxidants; Biological Assay; Breathing; Carcinogenicity Tests; Carcinogens; Cells; Chemicals; Confocal Microscopy; Development; Dominant-Negative Mutation; Down-Regulation; Early Diagnosis; Electron Spin Resonance Spectroscopy; Embryo; Enzymes; Epidemiology; Epithelial Cells; Fibroblasts; Gene Expression Regulation; Generations; Goals; Human; Hydrogen Peroxide; Hydroxyl Radical; I Kappa B-Alpha; In Vitro; Inbred BALB C Mice; Intervention; Investigation; Link; Luciferases; Malignant Neoplasms; Manganese Superoxide Dismutase; Measures; Mediating; Mediator of activation protein; Methods; Mitochondria; Molecular; Mus; NADPH Oxidase; Nature; Nickel; Nuclear; Nude Mice; Plasmids; Play; Prevention strategy; Protein Overexpression; Reaction; Reactive Oxygen Species; Reporter; Research; Risk Assessment; Role; Signal Transduction; Signaling Protein; Source; Spin Trapping; Structure of parenchyma of lung; Superoxides; Techniques; Testing; Transfection; Transgenic Mice; Tumor Promotion; activating transcription factor; cancer risk; carcinogenesis; catalase; cell transformation; in vivo; nuclear factors of activated T-cells; overexpression; response; transcription factor; tumorigenesis

Nickel-containing compounds are human carcinogens. The mechanisms of their carcinogenic actions remain to be investigated. Recent studies have indicated that reactive oxygen species (ROS) may play an important role. We hypothesize that nickel induces generation of ROS, which activate nuclear transcription factors, leading to cell transformation and tumorigenesis. Specific Aim 1 will detect and identify ROS generated in human bronchial epithelial cells (BEAS-2B) and mouse embryo fibroblast cells exposed to nickel compounds and investigate the mechanism involved. We hypothesize that nickel (Ni3S2 and NiCl2) can stimulate the cells to activate NADPH oxidase via cdc42 and p47phox to produce superoxide radical, which is then converted to hydrogen peroxide and hydroxyl radical. Specific Aim 2 will test the hypothesis that ROS are required for activation of NFAT and NFkappaB in cells and in vivo in response to nickel compounds. The role of ROS in nickel-induced activation of NFAT and NFkappaB in cells will be evaluated by co-transfection of NFkappaB-luciferase or NFAT-luciferase reporter plasmids and specific ROS scavenger enzymes. For in vivo study, BALB/c transgenic mice with alternation of antioxidant enzymes or NADPH oxidase (ROS generating enzyme) will be employed. Specific Aim 3 will Investigate the role of ROS, NFAT and NFkappaB in nickel-induced cell transformation and tumorigenesis. We hypothesize that ROS activate transcription factors and cause cell transformation and tumorigenesis. We will use overexpression of DN-NFAT, DN-IkappaBalpha and DN- IKKbeta to investigate the involvement of NFAT and NFkappaB in nickel-cell transformation and induced tumorigenesis. The role of ROS will be investigated using specific antioxidant enzyme expressions and NADPH oxidase alternation. We anticipate that nickel causes activation of NFAT and NFkappaB through ROS reactions, leading to cell transformation and tumorigenesis. We attempt to link the cell transformation and tumorigenesis with specific transcription factors and specific reactive oxygen species. The results obtained from this proposal will elucidate the role of ROS and NFAT/NFkappaB signaling in Ni compounds-induced carcinogenesis. The long term goals are to provide a fundamental understanding concerning the mechanism of carcinogenic actions of Ni; to fill a need for the mechanistic information of cancer risk assessment for exposure; to propose methods for early detection; and to develop intervention and prevention strategies. Nickel-containing compounds are human carcinogens. This project will investigate the mechanism of Ni-induced carcinogenesis by testing the hypothesis that nickel induces generation of ROS, which activate nuclear transcription factors, leading to cell transformation and tumorigenesis. The long term goals are to understand the mechanism of Ni-carcinogenesis; to propose methods for early detection; and to develop intervention and prevention strategies.

含镍化合物是人类致癌物。他们的机制 致癌作用仍有待调查。最近的研究表明， 活性氧（ROS）可能起重要作用。我们假设镍 诱导ROS的产生，其激活核转录因子，导致细胞凋亡。 转化和肿瘤发生。Specific Aim 1将检测和识别产生的ROS 人支气管上皮细胞（BEAS-2B）和小鼠胚胎成纤维细胞 暴露于镍化合物，并研究所涉及的机制。我们假设 镍（Ni 3S 2和NiCl 2）可以刺激细胞激活NADPH氧化酶， cdc 42和p47 phox产生超氧自由基，然后将其转化为氢 过氧化物和羟基自由基。具体目标2将检验ROS是 在细胞和体内响应镍激活NFAT和NF κ B所需 化合物.活性氧在镍诱导的NFAT和NF κ B活化中的作用 通过共转染NF κ B-荧光素酶或NFAT-荧光素酶来评价细胞 报告质粒和特异性ROS清除酶。对于体内研究，BALB/c 抗氧化酶或NADPH氧化酶（ROS）交替的转基因小鼠 产生酶）。具体目标3将研究ROS的作用， NFAT和NF κ B在镍诱导的细胞转化和肿瘤发生中的作用我们 假设ROS激活转录因子并引起细胞转化， 肿瘤发生我们将使用DN-NFAT、DN-I κ B α和DN-κ B α的过表达。 IKKbeta研究NFAT和NF κ B在镍细胞中的参与 转化和诱导肿瘤发生。ROS的作用将使用 特异性抗氧化酶表达和NADPH氧化酶改变。我们预计 镍通过ROS反应激活NFAT和NF κ B，导致 细胞转化和肿瘤发生。我们试图将细胞转化和 肿瘤发生与特异性转录因子和特异性活性氧有关。 从这个提议中获得的结果将阐明ROS的作用， NFAT/NF κ B信号在镍化合物诱导的致癌作用中的作用长期 目标是提供一个基本的了解机制， 镍的致癌作用;以满足对癌症风险机制信息的需求 评估接触情况;提出早期检测方法;并制定 干预和预防战略。含镍化合物是人类致癌物。该项目将调查 镍诱导的致癌机制，通过测试镍诱导的假说， 产生活性氧，激活核转录因子，导致细胞 转化和肿瘤发生。长期目标是了解 镍致癌机制;提出早期检测的方法;并开发 干预和预防战略。

项目成果

Tungsten carbide-cobalt particles activate Nrf2 and its downstream target genes in JB6 cells possibly by ROS generation.

• DOI: 10.1615/jenvironpatholtoxicoloncol.v29.i1.60
• 发表时间: 2010
• 期刊: Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer
• 作者: Xing-dong Zhang;Jinshun Zhao;L. Bowman;Xianglin Shi;V. Castranova;M. Ding

Cyanidin-3-glucoside inhibits UVB-induced oxidative damage and inflammation by regulating MAP kinase and NF-κB signaling pathways in SKH-1 hairless mice skin.

• DOI: 10.1016/j.taap.2014.06.028
• 发表时间: 2014-10-01
• 期刊: TOXICOLOGY AND APPLIED PHARMACOLOGY
• 影响因子: 3.8
• 作者: Pratheeshkumar, Poyil;Son, Young-Ok;Wang, Xin;Divya, Sasidharan Padmaja;Joseph, Binoy;Hitron, John Andrew;Wang, Lei;Kim, Donghern;Yin, Yuanqin;Roy, Ram Vinod;Lu, Jian;Zhang, Zhuo;Wang, Yitao;Shi, Xiang Lin
• 通讯作者: Shi, Xiang Lin

Epigenetic targets of arsenic: emphasis on epigenetic modifications during carcinogenesis.

• DOI: 10.1615/jenvironpatholtoxicoloncol.2014012066
• 发表时间: 2015
• 期刊: Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer
• 作者: R. Roy;Young-Ok Son;P. Pratheeshkumar;Lei Wang;J. A. Hitron;Sasidharan Padmaja Divya;Rakesh D;Donghern Kim;Yuan-qin Yin;Zhuo Zhang;Xianglin Shi

Nickel-induced down-regulation of ΔNp63 and its role in the proliferation of keratinocytes.

镍诱导的αNp63 下调及其在角质形成细胞增殖中的作用。

• DOI: 10.1016/j.taap.2011.03.024
• 发表时间: 2011
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Zhang,Zhuo;Li,Wenqi;Cheng,Senping;Yao,Hua;Zhang,Fan;Chang,Qingshan;Ke,Zunji;Wang,Xin;Son,Young-Ok;Luo,Jia;Shi,Xianglin
• 通讯作者: Shi,Xianglin