Vitamin D and Colon Cancer
Vitamin D and Colon Cancer
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DOI：
10.1007/978-1-60327-303-9_14
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发表时间：
2010
期刊：
影响因子：
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通讯作者：
H. Cross;M. Peterlik
中科院分区：
文献类型：
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作者：
H. Cross;M. Peterlik
维生素 D 预防结肠癌的作用可以追溯到 1,25-二羟基维生素 D3[1,25-(OH)2D] 在控制结肠上皮细胞增殖、分化和凋亡中的作用。人结肠细胞表达CYP27B1编码的25(OH)D-1α-羟化酶，因此能够将25-羟基维生素D[25(OH)D]转化为1,25(OH)2D。在维生素 D 不足的情况下，25(OH)2D 的利用率较低，因此结肠细胞中的 CYP27B1 活性可能不足以达到防止肿瘤细胞生长所需的 1,25(OH)2D 组织浓度。结肠肿瘤向高分化和中分化癌症的进展与 CYP27B1 mRNA 表达的显着增加相关。因此，结肠癌细胞仍可能产生足够的1,25(OH)2D来阻止或延缓肿瘤的进一步生长。然而，在进展为更高级别的恶性肿瘤期间，由于 CYP27B1 活性低以及分解代谢 CYP24A1 编码的 25(OH)D-24-羟化酶的优势，1,25(OH)2D 的生长控制效率会降低。有证据表明，CYP27B1 和 CYP24A1 表达的分化依赖性变化是基因活性差异表观遗传调控的结果。我们最近的研究结果表明，诱导 CYP27B1 和/或 CYP24A1 表达适当变化的因素可以增强维生素 D 的化学预防潜力。在采用典型“西式”饮食的小鼠中，膳食钙含量从 0.04% 增加到 0.90%，同时 CYP24A1mRNA 表达减少高达 90%。 17β-雌二醇在患有腺瘤性息肉的绝经后妇女的直肠粘膜中诱导CYP27B1。植物雌激素金雀异黄素不仅可以减少小鼠和人类结肠癌细胞系中的 CYP24A1，还可以上调 CYP27B1mRNA。最后，我们确定叶酸是小鼠结肠中 CYP24A1 活性的有效抑制剂。这些发现为提倡摄入足够的钙、叶酸和植物雌激素作为预防人类结直肠癌的有效措施提供了理论基础。
Protection from colon cancer by vitamin D can be traced to the role of 1,25-dihydroxyvitamin D3[1,25-(OH)2D] in controlling proliferation, differentiation, and apoptosis of colonic epithelial cells. Human colonocytes express theCYP27B1-encoded 25(OH)D-1α-hydroxylase and therefore are able to convert 25-hydroxyvitamin D[25(OH)D] to 1,25(OH)2D. In vitamin D insufficiency, availability of 25(OH)D is low, so that CYP27B1 activity in colonocytes may be not high enough to achieve tissue concentrations of 1,25(OH)2D necessary to prevent tumor cell growth. Progression of colon tumors to well and moderately differentiated cancers is associated with a considerable increase inCYP27B1mRNA expression. Thus, colon carcinoma cells may still produce enough 1,25(OH)2D to halt or retard further tumor growth. However, during progression to higher grades of malignancy, the efficiency of growth control by 1,25(OH)2D is diminished due to lowCYP27B1activity and by the predominance of the catabolicCYP24A1-encoded 25(OH)D-24-hydroxylase. There is evidence that the differentiation-dependent change inCYP27B1andCYP24A1expression is the result of differential epigenetic regulation of gene activity.Results from our recent studies suggest that the chemopreventive potential of vitamin D can be augmented by factors that induce appropriate changes inCYP27B1and/orCYP24A1expression. In mice on a typical “Western style” diet, an increase in dietary calcium from 0.04 to 0.90% was accompanied by an up to 90% reduction ofCYP24A1mRNA expression. 17β-Estradiol inducedCYP27B1in the rectal mucosa of postmenopausal women with adenomatous polyps. The phytoestrogen genistein not only reducedCYP24A1but also up-regulatedCYP27B1mRNA in mice as well as in a human colon cancer cell line. Finally, we identified folate as a potent suppressor ofCYP24A1activity in the mouse colon. These findings provide a rationale for advocating adequate intake levels of calcium, folate, and phytoestrogens as an effective measure for prevention of colorectal cancer in humans.