AhR-mediated changes in global gene expression in rat liver progenitor cells
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TOXICOGENOMICS
AhR-mediated changes in global gene expression in rat liver progenitor cells Dagmar Faust • Jan Vondra´cˇek • Pavel Krcˇma´rˇ • Lenka Sˇmerdova´ • Jirˇina Procha´zkova´ • Eva Hruba´ • Petra Hulinkova´ • Bernd Kaina • Cornelia Dietrich • Miroslav Machala
Received: 8 May 2012 / Accepted: 13 November 2012 Ó Springer-Verlag Berlin Heidelberg 2012
Dagmar Faust and Jan Vondra´cˇek contributed equally to the present work.
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-b 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.
Electronic supplementary material The online version of this article (doi:10.1007/s00204-012-0979-z) contains supplementary material, which is available to authorized users.
Keywords Aryl hydrocarbon receptor TCDD PCB 126 Gene expression 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
D. Faust B. Kaina C. Dietrich (&) Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131 Mainz, Germany e-mail: [email protected] J. Vondra´cˇek L. Sˇmerdova´ J. Procha´zkova´ Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 61137 Brno, Czech Republic P. Krcˇma´rˇ E. Hruba´ P. Hulinkova´ M. Machala (&) Department of Toxicology, Pharmacology, and Immunopharmacology, Veterinary Research Institute, Hudcova 70, 62100 Brno, Czech Repu
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