J Christopher Corton, Victoria Ledbetter, Samuel M Cohen, Ella Atlas, Carole L Yauk, Jie Liu
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引用次数: 0
Abstract
High-throughput transcriptomics (HTTr) is increasingly being used to identify molecular targets of chemicals that can be linked to adverse outcomes. Cell proliferation 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 cell proliferation (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 cell proliferation in 1) 367 tumor vs. normal surrounding tissue comparisons from 6 human organs, 2) MCF-7 cells after activation of ER, 3) after partial hepatectomy in mice and rats, and 4) the livers of mice after exposure to nongenotoxic hepatocarcinogens. The biomarker identified suppression of CP 1) under conditions of p53 activation by DNA damaging agents in human cells, 2) in human A549 lung cells exposed to therapeutic anticancer kinase inhibitors (dasatinib, nilotnib) and 3) 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 cell proliferation status after exposure to chemicals in human cells or in rodent tissues.
期刊介绍:
The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology.
The primary focus of Toxicological Sciences is on original research articles. The journal also provides expert insight via contemporary and systematic reviews, as well as forum articles and editorial content that addresses important topics in the field.
The scope of Toxicological Sciences is focused on a broad spectrum of impactful toxicological research that will advance the multidisciplinary field of toxicology ranging from basic research to model development and application, and decision making. Submissions will include diverse technologies and approaches including, but not limited to: bioinformatics and computational biology, biochemistry, exposure science, histopathology, mass spectrometry, molecular biology, population-based sciences, tissue and cell-based systems, and whole-animal studies. Integrative approaches that combine realistic exposure scenarios with impactful analyses that move the field forward are encouraged.