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The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1α in mice

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Abstract

Chemotherapy-induced intestinal damage is a very important dose-limiting side effect for which there is no definitive prophylaxis or treatment. This is in part due to the lack of understanding of its pathophysiology and impact on intestinal differentiation. The objective of this study was to investigate the gene expression of the small intestinal transcription factors HNF-1α, Cdx2, GATA-4 in an experimental model of methotrexate (MTX)-induced intestinal damage, and to correlate these alterations with histological damage, epithelial proliferation and differentiation. HNF-1α, Cdx2 and GATA-4 are critical transcription factors in epithelial differentiation, and in combination they act as promoting factors of the sucrase–isomaltase (SI) gene, an enterocyte-specific differentiation marker which is distinctly downregulated after MTX treatment. Mice received two doses of MTX i.v. on two consecutive days and were sacrificed 1, 3 and 7 or 9 days after final injection. Segments of the jejunum were taken for morphological, immunohistochemical and quantitative analyses. Intestinal damage was most severe at day 3 and was associated with decreased expression of the transcriptional factors HNF-1α, Cdx2 and GATA-4, which correlated well with decreased expression of SI, and seemed inversely correlated with enhanced proliferation of epithelial crypt cells. During severe damage, the epithelium was preferentially concerned with proliferation rather than differentiation, most likely in order to restore the small intestinal barrier function rather than maintaining its absorptive function. Since HNF-1α, Cdx2 and GATA-4 are critical for intestine-specific gene expression and therefore crucial in epithelial differentiation, these results may explain, at least in part, why intestinal differentiation is compromised during MTX treatment.

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Abbreviations

Cdx2:

Caudal-related homeobox transcription factor

HNF-1α:

Hepatocyte nuclear factor-1 alpha

IHC:

Immunohistochemistry

MTX:

Methotrexate

SI:

Sucrase–isomaltase

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Acknowledgements

We thank Dr. K.Y. Yeh for kindly providing the rabbit polyclonal anti-rat sucrase–isomaltase antiserum. This work was supported by a grant from Numico Research BV, Wageningen, The Netherlands and from the Sophia Foundation for Medical Research (SSWO). E.H.H.M.R. is supported by a fellowship of the Royal Netherlands Academy of Arts and Sciences.

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Authors and Affiliations

  1. Laboratory of Pediatrics, Division of Pediatric Gastro-enterology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Barbara A. E. de Koning, Dicky J. Lindenbergh-Kortleve, Hans A. Büller & Alexandra W. C. Einerhand

  2. Laboratory of Pediatrics, Division of Pediatric Oncology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Barbara A. E. de Koning & Rob Pieters

  3. Department of Pediatrics, University Hospital Groningen, Groningen, The Netherlands

    Edmond H. H. M. Rings

  4. Laboratory of Pediatrics, Division of Neontaology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands

    Ingrid B. Renes

  5. Laboratory of Pediatrics, Erasmus Medical Centre, Dr. Molewaterplein 50, 3015, Rotterdam, The Netherlands

    Barbara A. E. de Koning

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  1. Barbara A. E. de Koning
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Correspondence to Barbara A. E. de Koning.

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Koning, B.A.E.d., Lindenbergh-Kortleve, D.J., Pieters, R. et al. The effect of cytostatic drug treatment on intestine-specific transcription factors Cdx2, GATA-4 and HNF-1α in mice. Cancer Chemother Pharmacol 57, 801–810 (2006). https://doi.org/10.1007/s00280-005-0119-z

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  • DOI: https://doi.org/10.1007/s00280-005-0119-z

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