E-cadherin Mediates the Preventive Effect of Vitamin D3 in Colitis-associated Carcinogenesis
E-cadherin Mediates the Preventive Effect of Vitamin D3 in Colitis-associated Carcinogenesis
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E-钙粘蛋白介导维生素 D-3 在结肠炎相关癌发生中的预防作用
DOI：
10.1097/mib.0000000000001209
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发表时间：
2017-09-01
影响因子：
4.9
通讯作者：
Qian, Jiaming
中科院分区：
文献类型：
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作者：
Xin, Yu;He, Longmei;Qian, Jiaming
维生素D - 3有助于减轻或预防炎症及癌变。在此，我们评估了维生素D - 3对结肠炎相关癌变是否具有预防作用。通过给小鼠注射氧化偶氮甲烷（AOM），随后给予葡聚糖硫酸钠（DSS），来模拟结肠炎相关结肠癌。在AOM处理前或DSS处理后立即（60 IU剂量组处理后）开始补充不同剂量（15、30、60国际单位/克体重/周）的维生素D - 3，并持续至实验结束。饮食中补充维生素D - 3以剂量依赖的方式显著减少了肿瘤数量和肿瘤负荷。值得注意的是，无论在AOM - DSS处理之前还是之后给予，高剂量的维生素D - 3对癌变均显示出显著的预防效果。在结肠中，与对照组相比，维生素D - 3处理组在抑制β - 连环蛋白及其下游靶基因细胞周期蛋白D1的表达后，细胞增殖减少。在体外实验中，维生素D - 3降低了β - 连环蛋白的转录活性和核内水平，同时增加了E - 钙黏蛋白的表达及其与β - 连环蛋白的结合亲和力。此外，补充维生素D - 3可挽救小鼠结肠中E - 钙黏蛋白的表达抑制。综上所述，我们的结果表明，维生素D - 3在AOM - DSS小鼠模型中能有效抑制结肠癌变。我们的研究结果进一步表明，E - 钙黏蛋白的上调有助于维生素D - 3对β - 连环蛋白活性的预防作用。
Vitamin D-3 is beneficial in ameliorating or preventing inflammation and carcinogenesis. Here, we evaluated if vitamin D-3 has a preventive effect on colitis-associated carcinogenesis. Administration of azoxymethane (AOM), followed with dextran sulfate sodium (DSS), was used to simulate colitis-associated colon cancer in mice. The supplement of vitamin D-3 at different dosages (15, 30, 60 IU.g(-1).w(-1)), started before AOM or immediately after DSS treatment (post 60), was sustained to the end of the experiment. Dietary vitamin D-3 significantly reduced the number of tumors and tumor burden in a dose-dependent manner. Of note, vitamin D-3 in high doses showed significant preventive effects on carcinogenesis regardless of administration before or after AOM-DSS treatment. Cell proliferation decreased in vitamin D-3 groups compared with the control group after inhibition of expression of beta-catenin and its downstream target gene cyclin D1 in the colon. In vitro, vitamin D-3 reduced the transcriptional activity and nuclear level of beta-catenin, and it also increased E-cadherin expression and its binding affinity for beta-catenin. Moreover, repression of E-cadherin was rescued by supplemental vitamin D-3 in mouse colons. Taken together, our results indicate that vitamin D-3 effectively suppressed colonic carcinogenesis in the AOM-DSS mouse model. Our findings further suggest that upregulation of E-cadherin contributes to the preventive effect of vitamin D-3 on beta-catenin activity.