Center for Computational Toxicology and Exposure, US Environmental Protection Agency, Research Triangle Park, NC 27711, United States.
Department of Pathology and Microbiology and Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 69198-3135, United States.
Toxicol Sci. 2024 Oct 1;201(2):174-189. doi: 10.1093/toxsci/kfae102.
High-throughput transcriptomics (HTTr) is increasingly being used to identify molecular targets of chemicals that can be linked to adverse outcomes. Cell proliferation (CP) is an important key event in chemical carcinogenesis. Here, we describe the construction and characterization of a gene expression biomarker that is predictive of the CP status in human and rodent tissues. The biomarker was constructed from 30 genes known to be increased in expression in prostate cancers relative to surrounding tissues and in cycling human MCF-7 cells after estrogen receptor (ER) agonist exposure. Using a large compendium of gene expression profiles to test utility, the biomarker could identify increases in CP in (i) 308 out of 367 tumor vs. normal surrounding tissue comparisons from 6 human organs, (ii) MCF-7 cells after activation of ER, (iii) after partial hepatectomy in mice and rats, and (iv) the livers of mice and rats after exposure to nongenotoxic hepatocarcinogens. The biomarker identified suppression of CP (i) under conditions of p53 activation by DNA damaging agents in human cells, (ii) in human A549 lung cells exposed to therapeutic anticancer kinase inhibitors (dasatinib, nilotnib), and (iii) in the mouse liver when comparing high levels of CP at birth to the low background levels in the adult. The responses using the biomarker were similar to those observed using conventional markers of CP including PCNA, Ki67, and BrdU labeling. The CP biomarker will be a useful tool for interpretation of HTTr data streams to identify CP status after exposure to chemicals in human cells or in rodent tissues.
高通量转录组学（HTTr）越来越多地被用于鉴定与不良结果相关的化学物质的分子靶标。细胞增殖（CP）是化学致癌作用中的一个重要关键事件。在这里，我们描述了一种基因表达生物标志物的构建和特征，该标志物可预测人源和啮齿动物组织中 CP 的状态。该生物标志物由 30 个基因构建而成，这些基因在前列腺癌组织中相对于周围组织以及在雌激素受体（ER）激动剂暴露后的人 MCF-7 细胞中表达增加。使用大量的基因表达谱来测试其效用，该生物标志物可以识别（i）来自 6 个人体器官的 367 个肿瘤与正常周围组织比较中的 308 个 CP 增加，（ii）ER 激活后的 MCF-7 细胞，（iii）在小鼠和大鼠的部分肝切除后，以及（iv）在暴露于非遗传毒性肝致癌剂后的小鼠和大鼠肝脏中的 CP 增加。该生物标志物鉴定了 CP 的抑制作用（i）在人细胞中 DNA 损伤剂激活 p53 的情况下，（ii）在暴露于治疗性抗癌激酶抑制剂（达沙替尼，尼罗替尼）的人 A549 肺细胞中，以及（iii）在比较出生时高 CP 水平与成年时低背景水平的小鼠肝脏中。使用生物标志物的反应与使用 PCNA、Ki67 和 BrdU 标记等传统 CP 标志物观察到的反应相似。CP 生物标志物将是解释暴露于化学物质后人类细胞或啮齿动物组织中 CP 状态的 HTTr 数据流的有用工具。
