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  Transcriptomic responses generated by hepatocarcinogens in a battery of liver-based in vitro models

Doktorova, T. Y., Yildirimman, R., Vinken, M., Vilardell, M., Vanhaecke, T., Gmuender, H., et al. (2013). Transcriptomic responses generated by hepatocarcinogens in a battery of liver-based in vitro models. Carcinogenesis, 34(6), 1393-402. doi:10.1093/carcin/bgt054.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0018-D6E7-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0018-D6E9-9
Genre: Journal Article

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2014
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© 2014 Oxford University Press
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 Creators:
Doktorova, T. Y., Author
Yildirimman, R.1, Author              
Vinken, M., Author
Vilardell, M.2, Author              
Vanhaecke, T., Author
Gmuender, H., Author
Bort, R., Author
Brolen, G., Author
Holmgren, G., Author
Li, R., Author
Chesne, C., Author
van Delft, J., Author
Kleinjans, J., Author
Castell, J., Author
Bjorquist, P., Author
Herwig, R.1, Author              
Rogiers, V., Author
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479648              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              

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Free keywords: Animals Carcinogens/pharmacology/*toxicity Cell Line, Tumor Embryonic Stem Cells/drug effects Gene Expression/drug effects Gene Expression Profiling Hep G2 Cells Hepatocytes/*drug effects Humans Liver/*drug effects Liver Neoplasms Mutagens/pharmacology/*toxicity Rats Rats, Sprague-Dawley Transcriptome/*drug effects Tumor Suppressor Protein p53/drug effects
 Abstract: As the conventional approach to assess the potential of a chemical to cause cancer in humans still includes the 2-year rodent carcinogenicity bioassay, development of alternative methodologies is needed. In the present study, the transcriptomics responses following exposure to genotoxic (GTX) and non-genotoxic (NGTX) hepatocarcinogens and non-carcinogens (NC) in five liver-based in vitro models, namely conventional and epigenetically stabilized cultures of primary rat hepatocytes, the human hepatoma-derived cell lines HepaRG and HepG2 and human embryonic stem cell-derived hepatocyte-like cells, are examined. For full characterization of the systems, several bioinformatics approaches are employed including gene-based, ConsensusPathDB-based and classification analysis. They provide convincingly similar outcomes, namely that upon exposure to carcinogens, the HepaRG generates a gene classifier (a gene classifier is defined as a selected set of characteristic gene signatures capable of distinguishing GTX, NGTX carcinogens and NC) able to discriminate the GTX carcinogens from the NGTX carcinogens and NC. The other in vitro models also yield cancer-relevant characteristic gene groups for the GTX exposure, but some genes are also deregulated by the NGTX carcinogens and NC. Irrespective of the tested in vitro model, the most uniformly expressed pathways following GTX exposure are the p53 and those that are subsequently induced. The NGTX carcinogens triggered no characteristic cancer-relevant gene profiles in all liver-based in vitro systems. In conclusion, liver-based in vitro models coupled with transcriptomics techniques, especially in the case when the HepaRG cell line is used, represent valuable tools for obtaining insight into the mechanism of action and identification of GTX carcinogens.

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Language(s): eng - English
 Dates: 2013-01-152012-08-302013-02-022013-02-072013
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: Other: 23393228
DOI: 10.1093/carcin/bgt054
ISSN: 1460-2180 (Electronic)0143-3334 (Linking)
URI: http://www.ncbi.nlm.nih.gov/pubmed/23393228http://carcin.oxfordjournals.org/content/34/6/1393.full.pdf
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Title: Carcinogenesis
Source Genre: Journal
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Publ. Info: London [etc. : IRL Press]
Pages: - Volume / Issue: 34 (6) Sequence Number: - Start / End Page: 1393 - 402 Identifier: ISSN: 0143-3334
CoNE: https://pure.mpg.de/cone/journals/resource/954925472375