Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands
Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands
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DOI：
10.1016/j.toxlet.2011.07.011
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发表时间：
2011-10-10
影响因子：
3.5
通讯作者：
Machala, Miroslav
中科院分区：
文献类型：
--
作者：
Hruba, Eva;Vondracek, Jan;Machala, Miroslav
致癌性多环芳烃（PAH）被认为是有效的诱变剂和芳基烃受体（AhR）的配体，已被认为在前列腺癌发生中发挥重要作用。为了评估前列腺细胞中PAHs的基因毒性和AhR介导的活性之间的复杂关系，我们选择苯并[a]芘（BaP）和2,3,7,8-四氯二苯并-二恶英（TCDD）分别作为模型基因毒性和非基因毒性AhR配体，通过微阵列分析探索LNCaP细胞中基因表达的整体变化。我们鉴定出 112 个基因在用 BaP、TCDD 或两种化合物处理 24 小时的细胞中存在差异表达。我们的数据表明，BaP 和 TCDD 对 LNCaP 细胞转录组的影响显着重叠，因为超过 64% 的显着上调基因和 47% 的下调基因同样受到两种 AhR 配体的影响。这表明在前列腺癌细胞模型 LNCaP 中，AhR 的激活在 BaP 的非基因毒性作用中发挥了重要作用。两种 AhR 配体均抑制与细胞周期进展、DNA 复制、纺锤体组装检查点或 DNA 修复相关的基因表达，这可能继发于细胞周期进展的抑制。相比之下，我们发现 Wnt5a（前列腺癌进展的重要调节因子）最早在暴露于两种 AhR 配体后 6 小时就被诱导。 AhR 配体诱导的 Wnt5a 上调以及其他观察到的基因表达变化可能进一步有助于增强前列腺癌细胞的细胞可塑性。 (C) 2011 Elsevier Ireland Ltd. 保留所有权利。
Carcinogenic polycyclic aromatic hydrocarbons (PAHs) are known as efficient mutagens and ligands of the aryl hydrocarbon receptor (AhR), which has been suggested to play an important role in prostate carcinogenesis. In order to evaluate the complex relationship between the genotoxicity and the AhR-mediated activity of PAHs in prostate cells, we selected benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), as model genotoxic and nongenotoxic AhR ligands, respectively, to explore global changes in gene expression in LNCaP cells by microarray analysis. We identified 112 genes that were differentially expressed in cells treated for 24 h with BaP, TCDD or both compounds. Our data indicated that the impacts of BaP and TCDD on transcriptome of LNCaP cells significantly overlap, since over 64% of significantly up-regulated genes and 47% of down-regulated genes were similarly affected by both AhR ligands. This suggested that the activation of AhR played a prominent role in the nongenotoxic effects of BaP in the prostate carcinoma cell model LNCaP. Both AhR ligands suppressed expression of genes associated with cell cycle progression, DNA replication, spindle assembly checkpoint or DNA repair, which probably occurred secondary to inhibition of cell cycle progression. In contrast, we identified Wnt5a, an important regulator of prostate cancer progression, to be induced as early as 6 h after exposure to both AhR ligands. The AhR ligand-induced Wnt5a upregulation, together with other observed alterations of gene expression, may further contribute to enhanced cell plasticity of prostate carcinoma cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved.