Benzo[a]pyrene-Induced Changes in MicroRNA-mRNA Networks
Benzo[a]pyrene-Induced Changes in MicroRNA-mRNA Networks
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DOI：
10.1021/tx2003799
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发表时间：
2012-04-01
影响因子：
4.1
通讯作者：
van Delft, Joost H. M.
中科院分区：
文献类型：
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作者：
Lizarraga, Daneida;Gaj, Stan;van Delft, Joost H. M.
评估化合物对人类安全性的毒理学研究经常使用体外系统结合转录组分析来表征毒性反应。到目前为止，变化主要是在mRNA水平上研究的。最近，microRNA引起了人们的注意，因为它们是mRNA水平的强大负调节因子，因此可能负责调节与毒性有关的重要mRNA网络。本研究旨在确定可能的microRNA-mRNA网络作为基因表达水平上的遗传毒性损伤后的新的相互作用。我们使用苯并[a]芘（BaP），多环芳烃，作为模型遗传毒性/致癌化合物。我们分析了HepG 2细胞中mRNA和microRNA谱的时间依赖性效应，HepG 2细胞是一种广泛使用的人肝细胞系，表达活性p53，并能进行BaP的生物转化。观察到响应BaP的microRNA表达的变化，以及mRNA水平的多种变化。这些改变的mRNA中的许多是改变的microRNA的靶标。使用通路分析，我们评估了这种microRNA失调与遗传毒性的相关性。这揭示了8种似乎参与与遗传毒性相关的特定BaP反应途径的microRNA，例如凋亡信号传导，细胞周期阻滞，DNA损伤反应和DNA损伤修复。我们的结果特别强调了microRNA-29 b、microRNA-26 a-1* 和microRNA-122* 作为BaP反应中新参与者的潜力。因此，这项研究证明了一个集成的microRNA-mRNA方法的附加值，用于确定在体外人体模型中由BaP诱导的分子机制。
Toxicological studies assessing the safety of compounds for humans frequently use in vitro systems to characterize toxic responses in combination with transcriptomic analyses. Thus far, changes have mostly been investigated at the mRNA level. Recently, microRNAs have attracted attention because they are powerful negative regulators of mRNA levels and, thus, may be responsible for the modulation of important mRNA networks implicated in toxicity. This study aimed to identify possible microRNA-mRNA networks as novel interactions on the gene expression level after a genotoxic insult. We used benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, as a model genotoxic/carcinogenic compound. We analyzed time-dependent effects on mRNA and microRNA profiles in HepG2 cells, a widely used human liver cell line that expresses active p53 and is competent for the biotransformation of BaP. Changes in microRNA expression in response to BaP, in combination with multiple alterations of mRNA levels, were observed. Many of these altered mRNAs are targets of altered microRNAs. Using pathway analysis, we evaluated the relevance of such microRNA deregulations to genotoxicity. This revealed eight microRNAs that appear to participate in specific BaP-responsive pathways relevant to genotoxicity, such as apoptotic signaling, cell cycle arrest, DNA damage response, and DNA damage repair. Our results particularly highlight the potential of microRNA-29b, microRNA-26a-1*, and microRNA-122* as novel players in the BaP response. Therefore, this study demonstrates the added value of an integrated microRNA-mRNA approach for identifying molecular mechanisms induced by BaP in an in vitro human model.