title: AhR-mediated changes in global gene expression in rat liver progenitor cells.
abstract: Although the tumor-promoting effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), coplanar polychlorinated biphenyls (PCBs), and related compounds in liver tissue are primarily attributed to the activation of the aryl hydrocarbon receptor (AhR), the underlying molecular mechanisms are still unclear. Liver progenitor (oval) cells have been suggested to constitute a potential target for hepatocarcinogenic chemicals. To better understand AhR-driven pathways, we analyzed the transcriptional program in response to coplanar PCB 126 in contact-inhibited rat liver progenitor WB-F344 cells using high-density microarrays. After 6-h treatment, we identified 145 significantly deregulated genes considered to be direct AhR-dependent target genes. The number of differentially regulated genes increased to 658 and 968 genes after 24 and 72 h, respectively. Gene ontology analysis revealed that these genes were primarily involved in drug and lipid metabolism, cell cycle and growth control, cancer developmental processes, cell-cell communication, and adhesion. Interestingly, the Wnt and TGF-β signaling pathways, both being involved in developmental and tumorigenic processes, belonged to the most affected pathways. AhR- and ARNT-dependent regulation of selected target genes of interest was then confirmed using TCDD as a model AhR agonist, together with pharmacological inhibition of the AhR and by RNA-interference techniques. We demonstrated AhR-dependent regulation of emerging and novel AhR target genes, such as Fst, Areg, Hbegf, Ctgf, Btg2, and Foxq1. Among them, the transcription factor Foxq1, recently suggested to contribute to tumor promotion and/or progression, was found to be regulated at both mRNA and protein levels by AhR/ARNT activation.
authors.affiliation: Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Faust
authors.forename: Jan
authors.initials: J
authors.lastname: Vondráček
authors.forename: Pavel
authors.initials: P
authors.lastname: Krčmář
authors.forename: Lenka
authors.initials: L
authors.lastname: Smerdová
authors.forename: Jiřina
authors.initials: J
authors.lastname: Procházková
authors.forename: Eva
authors.initials: E
authors.lastname: Hrubá
authors.forename: Petra
authors.initials: P
authors.lastname: Hulinková
authors.forename: Bernd
authors.initials: B
authors.lastname: Kaina
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dietrich
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
mesh_terms: D000818:Animals; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004965:Estrogen Antagonists / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D055785:Gene Knockdown Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D004965:Estrogen Antagonists; D018336:Receptors, Aryl Hydrocarbon; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl