ToxSci Advance Access originally published online on May 28, 2003
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Toxicological Sciences 74, 32-42 (2003)
Copyright © 2003 by the Society of Toxicology
CARCINOGENICITY |
Gene Expression Patterns as Potential Molecular Biomarkers for Malignant Transformation in Human Keratinocytes Treated with MNNG, Arsenic, or a Metal Mixture
,1
* Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Institutes of Health, Bethesda, Maryland 20892;
Department of Biomedical Sciences and
Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Department of Environmental and Radiological Sciences, Colorado State University, Fort Collins, Colorado 80523
In previous studies, treatment with 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) enhanced malignant transformation of immortal human epidermal (RHEK-1) keratinocytes. In contrast, arsenic (As) alone or in a mixture of As, cadmium (Cd), chromium (Cr), and lead (Pb) inhibited this process. Microarray analysis showed unique gene expression patterns in RHEK-1 exposed to MNNG, As, or the metal mixture. From this analysis, we have selected 16 genes potentially involved in the enhancement or inhibition of transformation. These 16 genes, nine (IFN inducible protein 9-27, MAA A32, CCLB protein, integrin ß4, XRCC1, K8, K18, MT3, MAPKK6) of which were altered in a chemical-specific manner and seven (MIC1, bikunin, MTS1, BMP4, RAD23A, DOC2, vimentin) of which were commonly affected by the MNNG and As or mixture treatments, were examined for expression in detail by real-time RT-PCR. Qualitatively, both microarray and real-time RT-PCR analyses gave comparable results for 15 of 16 genes, i.e., genes were consistently induced or suppressed under the different treatment regimens when measured by either technique. Of the seven genes altered in their expression by multiple chemical treatments, five showed patterns consistent with a role in the transformation process, i.e., they were oppositely regulated in MNNG-transformed RHEK-1 cells (designated as OM3) as compared to the nonmalignant As- and mixture-exposed cells. Through time-course studies, we also identified markers whose expression correlates with acquisition of transformation-associated characteristics in OM3. Identification of a battery of genes altered during progressive transformation of RHEK-1 should aid in developing a mechanistic understanding of this process, as well as strengthening the utility of these genes as biomarkers.
Key Words: arsenic; metal mixture; gene expression; cDNA microarray; real-time RT-PCR; human keratinocytes; RHEK-1 cells.
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