Nioi Paul, Pardo Ingrid D R, Sherratt Philip J, Fielden Mark R, Gollub Jeremy, Nie Alex, Snyder Ronald D
The Schering-Plough Research Institute, Building S12-2603, 181 Passaic Avenue, Summit, NJ 07901, United States.
Chem Biol Interact. 2008 Nov 25;176(2-3):252-60. doi: 10.1016/j.cbi.2008.09.005.
Carcinogenicity of chemicals can currently only be evaluated in 2-year rodent bioassays. Therefore, the development of early biomarkers for carcinogenesis would result in substantial savings in time and expense. The current study investigates whether early changes in gene expression may be developed as markers for cancer. Animals were treated for 1 or 5 days with either non-genotoxic carcinogens or non-carcinogens and gene expression was analyzed by quantitative PCR (qPCR).We tested two gene signatures previously reported to detect non-genotoxic carcinogens. Using one gene signature it was confirmed that 3/3 nongenotoxic carcinogens and 2/2 non-carcinogens are correctly identified with data from 1 or 5 days of dosing. In contrast an alternative signature correctly identified 0/3 and 2/3 nongenotoxic carcinogens at 1 and 5 days of treatment, respectively and 2/2 non-carcinogens at both time-points. Additionally, we evaluated a novel panel of putative biomarker genes, from the literature, many of which have roles in cell growth and division, including myc, cdc2 and mcm6. These genes were significantly induced by non-genotoxic carcinogens and not by non-carcinogens. Using the average fold-induction across this panel, 2/3 non-genotoxic carcinogens were detected on both day 1 and day 5. These data support the idea that acute changes in gene expression may provide biomarkers for non-genotoxic carcinogenesis but also highlight interesting differences in the sensitivities of distinct gene signatures.
目前,化学品的致癌性只能通过为期两年的啮齿动物生物测定来评估。因此,开发早期致癌生物标志物将大幅节省时间和费用。当前的研究调查基因表达的早期变化是否可以作为癌症标志物。用非遗传毒性致癌物或非致癌物对动物进行1天或5天的处理,然后通过定量PCR(qPCR)分析基因表达。我们测试了先前报道的两种用于检测非遗传毒性致癌物的基因特征。使用一种基因特征,通过1天或5天给药的数据证实,3种非遗传毒性致癌物中的3种以及2种非致癌物中的2种被正确识别。相比之下,另一种特征在处理1天和5天时分别正确识别出0/3和2/3的非遗传毒性致癌物,在两个时间点均正确识别出2/2的非致癌物。此外,我们从文献中评估了一组新的假定生物标志物基因,其中许多基因在细胞生长和分裂中起作用,包括myc、cdc2和mcm6。这些基因被非遗传毒性致癌物显著诱导,而非致癌物则不会。利用该组基因的平均诱导倍数,在第1天和第5天都检测到了2/3的非遗传毒性致癌物。这些数据支持基因表达的急性变化可能为非遗传毒性致癌作用提供生物标志物这一观点,但同时也突出了不同基因特征在敏感性方面的有趣差异。