Carcinogenesis, Vol. 22, No. 9, 1429-1435,
September 2001
© 2001 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage
E.Kallay and P.Pietschmann should both be considered first authors.
1 Department of Pathophysiology,
2 Centre for Laboratory Animal Care and
3 Department of Medical and Chemical Laboratory Diagnostics, University of Vienna Medical School, Vienna,
4 Ludwig Boltzmann Institute for Aging Research, Vienna, Austria,
5 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University and
6 Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan
The vitamin D receptor knockout (VDR-KO) mouse presents with a skeletal phenotype typical for complete lack of genomic 1,25-dihydroxycholecalciferol effects. Our previous data from human colorectal tissue suggest that the steroid hormone and its receptor may have protective function against tumour progression. In order to investigate the relevance of the vitamin D system for pre-malignant site-directed changes in the colon, we characterized the amount and site-specific distribution of the VDR along the large intestine in wild-type (WT), heterozygote (HT) and KO mice. We also evaluated expression of proliferating cell nuclear antigen (PCNA), of cyclin D1 and the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress. In colon ascendens, proliferative cells were dispersed all along the crypt and expression levels of all three markers were high in WT mice. A decrease of VDR expression did not affect expression significantly. In colon descendens, however, fewer proliferative cells were solely located in the lower third of the crypt, and an inverse relationship between VDR reduction, PCNA positivity and cyclin D1 expression was found in HT and KO mice. In parallel to enhanced proliferation a highly significant increase of 8-OHdG positivity occurred. Therefore, the sigmoid colon of VDR-KO mice, fed on an appropriate lactose/calcium-enriched diet to alleviate impaired calcium homeostasis-related phenotypic changes, is an excellent model for investigating induction and prevention of pre-malignant changes in one of the hotspots for human colorectal cancer incidence.
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