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AhR-mediated changes in global gene expression in rat liver progenitor cells

  • Toxicogenomics
  • Published:
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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.

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Acknowledgments

Authors thank Dr. Robert Ivánek (Genomics and Bioinformatics Facility, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic) for help with Affymetrix microarray analysis. The present study was supported by grant No. 524/09/1337 from the Czech Science Foundation, the 7th EU framework program project SYSTEQ (grant No. 226694) and the Deutsche Forschungsgemeinschaft (Di793/3-1).

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Authors and Affiliations

  1. Institute of Toxicology, University Medical Center of the Johannes Gutenberg-University Mainz, Obere Zahlbacherstr. 67, 55131, Mainz, Germany

    Dagmar Faust, Bernd Kaina & Cornelia Dietrich

  2. Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 61137, Brno, Czech Republic

    Jan Vondráček, Lenka Šmerdová & Jiřina Procházková

  3. Department of Toxicology, Pharmacology, and Immunopharmacology, Veterinary Research Institute, Hudcova 70, 62100, Brno, Czech Republic

    Pavel Krčmář, Eva Hrubá, Petra Hulinková & Miroslav Machala

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  1. Dagmar Faust
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Correspondence to Cornelia Dietrich or Miroslav Machala.

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Dagmar Faust and Jan Vondráček contributed equally to the present work.

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Faust, D., Vondráček, J., Krčmář, P. et al. AhR-mediated changes in global gene expression in rat liver progenitor cells. Arch Toxicol 87, 681–698 (2013). https://doi.org/10.1007/s00204-012-0979-z

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