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Title: | Time- and concentration-dependent changes in gene expression induced by benzo(a)pyrene in two human cell lines, MCF-7 and HEPG2 |
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List of authors: | Hockley SL; Arlt VM; Brewer D; Giddings I; Phillips DH. |
Reference: | BMC Genomics, 7: 260 |
Year of Publication: | 2006 |
ISSN: | 1471-2164 |
Keywords: | Benzo(a)pyrene, microarrays, gene expression, carcinogenesis, RTqPCR |
Abstract: | The multi-step process of carcinogenesis may be more fully understood by characterizing gene expression changes induced in cells by carcinogens. In this study, expression microarrays were used to monitor the activity of 18,224 cDNA clones in MCF-7 and HepG2 exposed to the carcinogen benzo(a)pyrene (BaP) or its non-carcinogenic isomer benzo(e)pyrene (BeP). In total 202 clones were modulated by BaP (0.25-5.0 M; 6-48 h exposure) in MCF-7 cells and 127 in HepG2 cells, including 27 that were altered in both. In contrast, BeP did not induce any consistent gene expression changes at the same concentrations. Concentration- and time-dependent responses to BaP were seen in both cell lines by 2-Way ANOVA. Expression changes observed in both cell lines included genes involved in xenobiotic metabolism (e.g. CYP1B1, NQO1, MGST1, AKR1C1, AKR1C3, CPM), cell cycle regulation (e.g. CDKN1A), apoptosis/anti-apoptosis (e.g. BAX, IER3), chromatin assembly (e.g. histone genes), and oxidative stress response (e.g. TXNRD1). RTqPCR was used to validate microarray data. Phenotypic anchoring of the expression data to DNA adduct levels detected by 32P-postlabelling, cell cycle data and p53 protein expression identified a number of genes that limked to these biological outcomes, therefore strengthening the identification of target genes. The down-regulation of histone genes for example could be linked to the arrest of cells in S phase of the cell cycle. The MCF-7 expression profiles showed clearer correlations with the other phenotypic measurements, especially with the DNA adduct data. The overall response to BaP consisted of up-regulation of tumour suppressor genes and down-regulation of oncogenes promoting cell cycle arrest and apoptosis. Anti-apoptotic signaling was also evident that may increase cell survival and promote tumourigenesis. This study demonstrates that by investigating the time and concentration effect of carcinogens on gene expression related to other biological end-points gives greater insight into cellular responses to such compounds. |
PMID: | 17042939 |
Gene List: | CRUKDMF 15K Genome-wide Array CRUKDMF 6K Genome-wide Array |
Supplementary data: | Table 1 (MCF-7 and HEPG2 BaP Expression changes by 1.4-fold) Table 2 (HEPG2 2-way ANOVA) Table 3 (MCF-7 2-way ANOVA) Table 4 (MCF-7 and HEPG2 BeP Expression changes by 1.4-fold) Table 5a (EASE) Table 5b (EASE) Table 5c (EASE) Table 6 (qRT-PCR Data) |