Comparison of Gene Expression Profiles in HepG2 Cells Exposed to Arsenic, Cadmium, Nickel, and Three Model Carcinogens for Investigating the Mechanisms of Metal Carcinogenesis
Comparison of Gene Expression Profiles in HepG2 Cells Exposed to Arsenic, Cadmium, Nickel, and Three Model Carcinogens for Investigating the Mechanisms of Metal Carcinogenesis
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DOI：
10.1002/em.20438
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发表时间：
2009-01-01
影响因子：
2.8
通讯作者：
Okabe, Satoshi
中科院分区：
文献类型：
--
作者：
Kawata, Koji;Shimazaki, Ryuhei;Okabe, Satoshi
致癌作用是金属和类金属的重要慢性毒性，但其作用机制尚不清楚。比较致癌金属、类金属和模型致癌物诱导的基因表达模式，有助于深入了解它们的致癌机制。在这项研究中，我们研究了人类肝癌细胞系HepG 2中的基因表达变化，暴露于两种金属（镉和镍），一种类金属（砷）和三种模型致癌化学品N-二甲基亚硝胺（DMN），12-O-十四烷酰基佛波醇-3-乙酸酯（TPA）和四氯乙烯（TCE）后，使用含有8，795个人类基因的DNA微阵列。在砷、镉、镍暴露改变的基因中，有31-55%与我们实验中三种致癌化学物质暴露改变的基因重叠。特别是，金属和类金属与TPA和TCE在显著上调与细胞周期进展相关的基因方面具有某些特征，这可能在As，Cd和Ni致癌中起核心作用。这种基因表达改变的特点是部分抵消了细胞内积累的维生素C暴露的细胞，而细胞周期相关基因的数量增加，镉和镍暴露的细胞。在本实验条件下，活性氧对砷的细胞增殖机制有促进作用，而对其他两种重金属的细胞增殖机制有抑制作用。此外，根据Q-PCR的结果，癌基因PTTG I，这是上调的所有致癌化学品暴露在阵列实验中，可能是一个有用的生物标志物，评价无机致癌物的致癌作用。Environ.摩尔变异体50：46-59，2009. (C)2008 Wiley-Liss，Inc.
Carcinogenesis is an important chronic toxicity of metals and metalloids, although their mechanisms of action are still unclear. Comparison of gene expression patterns induced by carcinogenic metals, metalloids, and model carcinogens would give an insight into understanding of their carcinogenic mechanisms. In this study, we examined the gene expression alteration in human hepatoma cell line, HepG2, after exposing to two metals (cadmium and nickel), a metalloid (arsenic), and three model carcinogenic chemicals N-dimethylnitrosoamine (DMN), 12-O-tetradeconoylphorbol-3-acetate (TPA), and tetrachloroethylene (TCE) using DNA microarrays with 8,795 human genes. Of the genes altered by As, Cd, and Ni exposures, 31-55% were overlapped with those altered by three model carcinogenic chemical exposures in our experiments. In particular, the metals and metalloid shared certain characteristics with TPA and TCE in remarkable upregulations of the genes associated with progression of cell cycle, which might play a central role in As, Cd, and Ni carcinogenesis. This characteristic of gene expression alteration was partially counteracted by intracellular accumulation of vitamin C in As-exposed cells, whereas the number of cell-cycle associated genes was increased in Cd- and Ni-exposed cells. In our experimental conditions, ROS might have an accelerative effect on the cell proliferation mechanisms of As, but have an inhibitory effect on those of other two heavy metals. Furthermore, based on the results of Q-PCR, the oncogene PTTG I, which was upregulated by all carcinogenic chemical exposures in the array experiments, might be a useful biomarker for evaluation of the carcinogenesis of inorganic carcinogens. Environ. Mol. Mutagen. 50:46-59, 2009. (C) 2008 Wiley-Liss, Inc.