Diet-derived 25-hydroxyvitamin D3 activates vitamin D receptor target gene expression and suppresses EGFR mutant non-small cell lung cancer growth in vitro and in vivo.
Diet-derived 25-hydroxyvitamin D3 activates vitamin D receptor target gene expression and suppresses EGFR mutant non-small cell lung cancer growth in vitro and in vivo.
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饮食来源的25-羟基维生素D3激活维生素D受体靶基因表达，并抑制EGFR突变体非小细胞肺癌在体外和体内。
DOI：
10.18632/oncotarget.6493
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发表时间：
2016-01-05
期刊：
影响因子：
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通讯作者：
Hershberger PA
中科院分区：
文献类型：
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作者：
Verone-Boyle AR;Shoemaker S;Attwood K;Morrison CD;Makowski AJ;Battaglia S;Hershberger PA
流行病学研究表明维生素 D 状态是影响 EGFR 突变肺癌生长的一个因素。然而，缺乏维生素 D 在这种疾病中的生物学效应的实验室证据。为了填补这一知识空白，我们使用由从不吸烟者（EGFR 基因突变普遍存在）的肺癌病例构建的组织微阵列测定了人类肺癌中的维生素 D 受体 (VDR) 表达。在 19/19 EGFR 突变肿瘤中检测到核 VDR。 EGFR 外显子 19 缺失的肿瘤中的表达往往高于 EGFR L858R 突变的肿瘤。为了研究抗增殖活性和信号转导，使用维生素 D 的循环代谢物 25-羟基维生素 D3 (25D3) 处理 EGFR 突变型肺癌细胞。 25D3 以剂量依赖性方式抑制克隆生长。 CYP27B1 编码 1α-羟化酶 (1αOHase)，可将 25D3 转化为活性代谢物 1,25-二羟基维生素 D3 (1,25D3)。使用 VDR siRNA、CYP27B1 锌指核酸酶和维生素 D 途径药理学抑制剂的研究表明，25D3 以 VDR 依赖性方式调节基因表达，但并不严格要求 1αOHase 介导的 25D3 到 1,25D3 的转化。为了确定调节血清 25D3 水平对 EGFR 突变肺肿瘤异种移植物生长的影响，给小鼠喂食含有 100 或 10,000 IU 维生素 D3/kg 的饮食。高膳食维生素 D3 摄入量导致血清 25D3 升高并显着抑制肿瘤生长。没有观察到补充剂的毒性作用。这些结果确定 EGFR 突变型肺癌是一种维生素 D 反应性疾病，而饮食来源的 25D3 是一种直接的 VDR 激动剂和治疗剂。
Epidemiologic studies implicate vitamin D status as a factor that influences growth of EGFR mutant lung cancers. However, laboratory based evidence of the biological effect of vitamin D in this disease is lacking. To fill this knowledge gap, we determined vitamin D receptor (VDR) expression in human lung tumors using a tissue microarray constructed of lung cancer cases from never-smokers (where EGFR gene mutations are prevalent). Nuclear VDR was detected in 19/19 EGFR mutant tumors. Expression tended to be higher in tumors with EGFR exon 19 deletions than those with EGFR L858R mutations. To study anti-proliferative activity and signaling, EGFR mutant lung cancer cells were treated with the circulating metabolite of vitamin D, 25-hydroxyvitamin D3 (25D3). 25D3 inhibited clonogenic growth in a dose-dependent manner. CYP27B1 encodes the 1α-hydroxylase (1αOHase) that converts 25D3 to the active metabolite, 1,25-dihydroxyvitamin D3 (1,25D3). Studies employing VDR siRNA, CYP27B1 zinc finger nucleases, and pharmacologic inhibitors of the vitamin D pathway indicate that 25D3 regulates gene expression in a VDR-dependent manner but does not strictly require 1αOHase-mediated conversion of 25D3 to 1,25D3. To determine the effects of modulating serum 25D3 levels on growth of EGFR mutant lung tumor xenografts, mice were fed diets containing 100 or 10,000 IU vitamin D3/kg. High dietary vitamin D3 intake resulted in elevated serum 25D3 and significant inhibition of tumor growth. No toxic effects of supplementation were observed. These results identify EGFR mutant lung cancer as a vitamin D-responsive disease and diet-derived 25D3 as a direct VDR agonist and therapeutic agent.