Cellular and molecular effects of vitamin D on carcinogenesis.
Cellular and molecular effects of vitamin D on carcinogenesis.
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DOI：
10.1016/j.abb.2011.10.019
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发表时间：
2012-07-01
影响因子：
3.9
通讯作者：
Welsh, JoEllen
中科院分区：
文献类型：
--
作者：
Welsh, JoEllen
流行病学数据表明，多种癌症的发病率和严重程度与维生素 D 状态指数呈负相关。维生素 D 受体 (VDR) 在有致癌风险的上皮细胞中高表达，包括皮肤、乳房、前列腺和结肠中的上皮细胞，为维生素 D 状态影响致癌提供了直接的分子联系。与这一概念一致，VDR 通过其配体 1,25-二羟基维生素 D (1,25D) 激活会触发上皮细胞的全面基因组变化，从而有助于维持分化表型、抵抗细胞应激和保护基因组。许多上皮细胞还表达维生素 D 代谢酶 CYP27B1，该酶能够从循环维生素 D 代谢物 25-羟基维生素 D (25D) 自分泌生成 1,25D，从而将整体维生素 D 状态与细胞抗肿瘤作用紧密联系起来。此外，动物模型的临床前研究表明，膳食补充维生素 D 或长期使用 VDR 激动剂治疗可减少皮肤、结肠、前列腺和乳腺癌的肿瘤发展。相反，小鼠中 VDR 基因的缺失会改变增殖和凋亡之间的平衡，增加氧化性 DNA 损伤，并增强这些组织的癌变易感性。由于许多人类肿瘤中保留了 VDR 表达，因此维生素 D 状态可能是癌症患者癌症进展的重要调节剂。总的来说，这些观察结果强调了进一步确定 VDR 的分子作用以及人类对维生素 D 与癌症发生和进展相关的需求的必要性。
Epidemiologic data suggest that the incidence and severity of many types of cancer inversely correlates with indices of vitamin D status. The vitamin D receptor (VDR) is highly expressed in epithelial cells at risk for carcinogenesis including those resident in skin, breast, prostate and colon, providing a direct molecular link by which vitamin D status impacts on carcinogenesis. Consistent with this concept, activation of VDR by its ligand 1,25-dihydroxyvitamin D (1,25D) triggers comprehensive genomic changes in epithelial cells that contribute to maintenance of the differentiated phenotype, resistance to cellular stresses and protection of the genome. Many epithelial cells also express the vitamin D metabolizing enzyme CYP27B1 which enables autocrine generation of 1,25D from the circulating vitamin D metabolite 25-hydroxyvitamin D (25D), critically linking overall vitamin D status with cellular anti-tumor actions. Furthermore, pre-clinical studies in animal models has demonstrated that dietary supplementation with vitamin D or chronic treatment with VDR agonists decreases tumor development in skin, colon, prostate and breast. Conversely, deletion of the VDR gene in mice alters the balance between proliferation and apoptosis, increases oxidative DNA damage, and enhances susceptibility to carcinogenesis in these tissues. Because VDR expression is retained in many human tumors, vitamin D status may be an important modulator of cancer progression in persons living with cancer. Collectively, these observations have reinforced the need to further define the molecular actions of the VDR and the human requirement for vitamin D in relation to cancer development and progression.
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