Rieswijk Linda, Brauers Karen J J, Coonen Maarten L J, van Breda Simone G J, Jennen Danyel G J, Kleinjans Jos C S
Department of Toxicogenomics, Maastricht University, PO Box 616, 6200 MD Maastricht, Universiteitssingel 40, 6229 ER Maastricht, Netherlands and Netherlands Toxicogenomics Centre, PO Box 616, 6200 MD Maastricht, Universiteitssingel 40, 6229 ER Maastricht, Netherlands
Department of Toxicogenomics, Maastricht University, PO Box 616, 6200 MD Maastricht, Universiteitssingel 40, 6229 ER Maastricht, Netherlands and.
Mutagenesis. 2015 Nov;30(6):771-84. doi: 10.1093/mutage/gev036. Epub 2015 May 14.
Chemical carcinogenesis can be induced by genotoxic (GTX) or non-genotoxic (NGTX) carcinogens. GTX carcinogens have a well-described mode of action. However, the complex mechanisms by which NGTX carcinogens act are less clear and may result in conflicting results between species [e.g. Wy-14,643 (Wy)]. We hypothesise that common microRNA response pathways exist for each class of carcinogenic agents. Therefore, this study compares and integrates mRNA and microRNA expression profiles following short term acute exposure (24 and 48h) to three GTX [aflatoxin B1 (AFB1), benzo[a]pyrene (BaP) and cisplatin (CisPl)] or three NGTX (2,3,7,8-tetrachloordibenzodioxine (TCDD), cyclosporine A (CsA) and Wy) carcinogens in primary mouse hepatocytes. Discriminative gene sets, microRNAs (not for 24h) and processes were identified following 24 and 48h of exposure. From the three discriminative microRNAs found following 48h of exposure, mmu-miR-503-5p revealed to have an interaction with mRNA target gene cyclin D2 (Ccnd2 - 12444) which was involved in the discriminative process of p53 signalling and metabolism. Following exposure to NGTX carcinogens Mmu-miR-503-5p may have an oncogenic function by stimulating Ccnd2 possibly leading to a tumourigenic cell cycle progression. By contrast, after GTX carcinogen exposure it may have a tumour-suppressive function (repressing Ccnd2) leading to cell cycle arrest and to increased DNA repair activities. In addition, compound-specific microRNA-mRNA interactions [mmu-miR-301b-3p-Papss2 (for AFB1), as well as mmu-miR-29b-3p-Col4a2 and mmu-miR-24-3p-Flna (for BaP)] were found to contribute to a better understanding of microRNAs in cell cycle arrest and the impairment of the DNA damage repair, an important hallmark of GTX-induced carcinogenesis. Overall, our results indicate that microRNAs represent yet another relevant intracellular regulatory level in chemical carcinogenesis.
化学致癌作用可由遗传毒性（GTX）或非遗传毒性（NGTX）致癌物诱发。GTX致癌物具有明确的作用模式。然而，NGTX致癌物的作用机制较为复杂，尚不清楚，可能导致不同物种之间出现相互矛盾的结果[例如Wy-14,643（Wy）]。我们假设每类致癌剂都存在共同的微小RNA反应途径。因此，本研究比较并整合了原代小鼠肝细胞短期急性暴露（24小时和48小时）于三种GTX致癌物[黄曲霉毒素B1（AFB1）、苯并[a]芘（BaP）和顺铂（CisPl）]或三种NGTX致癌物[2,3,7,8-四氯二苯并二恶英（TCDD）、环孢素A（CsA）和Wy]后的mRNA和微小RNA表达谱。在暴露24小时和48小时后，确定了具有鉴别性的基因集、微小RNA（24小时暴露组未检测）和生物学过程。在暴露48小时后发现的三种具有鉴别性的微小RNA中，mmu-miR-503-5p显示与mRNA靶基因细胞周期蛋白D2（Ccnd2 - 12444）存在相互作用，该基因参与了p53信号传导和代谢的鉴别过程。暴露于NGTX致癌物后，Mmu-miR-503-5p可能通过刺激Ccnd2发挥致癌功能，可能导致致瘤性细胞周期进程。相比之下，在暴露于GTX致癌物后，它可能具有肿瘤抑制功能（抑制Ccnd2），导致细胞周期停滞并增加DNA修复活性。此外，还发现了化合物特异性的微小RNA-mRNA相互作用[mmu-miR-301b-3p-Papss2（针对AFB1），以及mmu-miR-29b-3p-Col4a2和mmu-miR-24-3p-Flna（针对BaP）]，这有助于更好地理解微小RNA在细胞周期停滞和DNA损伤修复受损中的作用，而DNA损伤修复受损是GTX诱导致癌作用的一个重要标志。总体而言，我们的结果表明，微小RNA代表了化学致癌作用中另一个相关的细胞内调节水平。
