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The dioxin/aryl hydrocarbon receptor mediates downregulation of osteopontin gene expression in a mouse model of gastric tumourigenesis

Abstract

The dioxin/aryl hydrocarbon receptor functions as a ligand-activated transcription factor regulating transcription of a battery of genes encoding primarily drug-metabolizing enzymes. Expression of a constitutively active mutant of the aryl hydrocarbon receptor (CA-AhR) in transgenic mice results in development of stomach tumours, correlating with increased mortality. We have used suppression subtractive hybridization techniques followed by macroarray analysis to elucidate which genes are differentially expressed during this process. In the glandular stomach of CA-AhR mice, we observed decreased mRNA expression of osteopontin (OPN), a noncollagenous protein of bone matrix that is also involved in several important functions including regulation of cytokine production, macrophage accumulation, cell motility and adhesion. Downregulated expression of OPN during tumour development was confirmed by RT–PCR and RNA blot analysis. Immunohistochemical analysis showed that this decrease was confined to the corpus region, correlating with the restricted localization of the tumours. Decreased OPN mRNA expression was also observed in other organs of CA-AhR mice. Taken together, these results show that OPN is negatively regulated by the dioxin receptor, and that downregulation of its expression correlates with development of stomach tumours in mice expressing a constitutively active mutant of dioxin receptor.

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Abbreviations

CYP1A1:

cytochrome P450 1A1

CA-AhR:

constitutively active aryl hydrocarbon receptor

ARNT:

arylhydrocarbon receptor nuclear translocator

NMO1:

NAD[P]H:menadione oxidoreductase 1

OPN:

osteopontin

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

XRE:

xenobiotic response element

SSH:

suppression subtractive hybridization

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Acknowledgements

We would like to thank Professor Ann F Chambers, University of Western Ontario and London Regional Cancer Centre, Canada, for providing us with osteopontin cDNA. This work was supported by the Swedish Cancer Society, The Foundation for Strategic Environmental Research, The Swedish Environmental Protection Agency (the ReproSafe programme) and The Swedish Council for Environment Agricultural Sciences and Spatial Planning.

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Correspondence to Lorenz Poellinger.

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Kuznetsov, N., Andersson, P., Gradin, K. et al. The dioxin/aryl hydrocarbon receptor mediates downregulation of osteopontin gene expression in a mouse model of gastric tumourigenesis. Oncogene 24, 3216–3222 (2005). https://doi.org/10.1038/sj.onc.1208529

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