Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage
Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage
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DOI：
10.1093/carcin/22.9.1429
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发表时间：
2001-09-01
期刊：
影响因子：
4.7
通讯作者：
Cross, HS
中科院分区：
文献类型：
--
作者：
Kallay, E;Pietschmann, P;Cross, HS
维生素D受体敲除（VDR-KO）小鼠表现出典型的骨骼表型，完全缺乏基因组1，25-二羟基胆钙化醇效应。我们以前从人类结直肠组织中获得的数据表明，类固醇激素及其受体可能对肿瘤进展具有保护作用。为了研究维生素D系统与结肠癌前病变的相关性，我们对野生型（WT）、杂合子（HT）和KO小鼠中VDR沿着大肠的数量和位点特异性分布进行了表征。我们还评估了增殖细胞核抗原（PCNA）、细胞周期蛋白D1的表达和氧化应激标志物8-羟基-2 '-脱氧鸟苷（8-OHdG）的水平。在升结肠中，增殖细胞沿沿着隐窝分散，WT小鼠中所有三种标志物的表达水平均较高。VDR表达的减少对表达没有显著影响。然而，在结肠降段，较少的增殖细胞仅位于隐窝的下三分之一，并且在HT和KO小鼠中发现VDR减少、PCNA阳性和cycfin D1表达之间呈反比关系。与增殖增强平行，发生了8-OHdG阳性的高度显著增加。因此，VDR-KO小鼠的乙状结肠，喂养适当的乳糖/钙丰富的饮食，以减轻受损的钙稳态相关的表型变化，是一个很好的模型，研究诱导和预防癌前病变的热点之一，人类结直肠癌的发病率。
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 cycfin 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 premalignant changes in one of the hotspots for human colorectal cancer incidence.