The dioxin/aryl hydrocarbon receptor mediates downregulation of osteopontin gene expression in a mouse model of gastric tumourigenesis.
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.
Kuznetsov
Nikolai V
NV
InDex Pharmaceuticals AB, Scheeles väg 1, S-171 77 Stockholm, Sweden.
Andersson
Patrik
P
Gradin
Katarina
K
Stein
Petra von
Pv
Dieckmann
Andreas
A
Pettersson
Sven
S
Hanberg
Annika
A
Poellinger
Lorenz
L
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D006838:Hydrocarbons; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D012313:RNA