Vitamin D3 Modulation of Inflammation and Lung Cancer Risk

在这个新的SPORE项目中提出的研究旨在为维生素D3- 基于方法的肺癌预防。我们最近证明，1，25-二羟维生素D3 [1，25（OH）2D 3]是维生素03的活性代谢物，可显著抑制肺癌细胞的生长， 拮抗核因子-κ B（NF-κ B）的作用。NF-κ B信号传导在炎症中起关键作用， 被证明是吸烟相关的肺部炎症和致癌的基础。综合来看，这表明 1，25（OH）_2D_3可能对肺癌的化学预防有一定的作用。因为全身1，25（OH）2D 3 由于其高钙血症诱导特性使给药复杂化，我们建议使用口服 补充维生素D3以安全地达到肺组织内的化学预防性1，25（OH）2D 3水平。 一旦摄入，维生素D3很容易转化为无毒的循环前体25（OH）D3， 随后在肺内通过表达CYP 27 B1的支气管上皮细胞转化为1，25（OH）2D 3 和肺泡巨噬细胞。确定维生素D3暴露对肺部炎症的影响， 肺癌风险，我们将：（目的1）利用我们的孢子肺肿瘤548例样本和数据 登记处，以及匹兹堡肺筛查研究（PLuSS）的180例病例和993例对照，以评估 维生素D3和NF-κ B通路基因变异、血清25（OH）D3水平与 肺癌;（目的2）使用来自150名PLuSS参与者的库存样本，以建立 25（OH）D3血清水平和痰中的炎症和肺癌风险生物标志物;（目的3）使用鼠 量化维生素D3状态对NNK诱导的肺癌发生和香烟影响的模型 吸烟诱导的肺部炎症，并检查香烟烟雾暴露对25（OH）D3的影响 维生素D3代谢酶的水平和表达;以及，（目标4）进行生物有效性研究， 维生素D3补充剂在肺癌风险增加的个体中。我们将评估是否 补充维生素D3可以纠正维生素D3缺乏症，还可以研究对炎症和肺癌的影响 痰中的风险生物标志物、循环炎症标志物和肺功能。

The studies proposed in this new SPORE project are designed to provide strong rationale for a vitamin D3- based approach to lung cancer prevention. We recently demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active metabolite of vitamin 03, significantly inhibits the growth of lung cancer cells and antagonizes nuclear factor-KB (NF-KB) action. NF-KB signaling plays a key role in inflammation, and has been shown to underlie smoking-associated lung inflammation and carcinogenesis. Together, this suggests that 1,25(OH)2D3 may be useful for chemoprevention of lung cancer. Because systemic 1,25(OH)2D3 administration is complicated by its hypercalcemia-inducing properties, we propose to use oral supplementation with vitamin D3 to safely achieve chemopreventive1,25(OH)2D3 levels within lung tissues. Upon ingestion, vitamin D3 is readily converted to the non-toxic circulating precursor, 25(OH)D3, which is subsequently converted to 1,25(OH)2D3 within the lung by CYP27B1-expressing bronchial epithelial cells and alveolar macrophages. To determine the impact of vitamin D3 exposure on pulmonary inflammation and lung cancer risk we will: (Aim 1) utilize samples and data from 548 cases from our SPORE Lung Tumor Registry, and 180 cases and 993 controls from the Pittsburgh Lung Screening Study (PLuSS) to evaluate the relationship between variation in vitamin D3 and NF-KB pathway genes, 25(OH)D3 serum levels, and risk of lung cancer; (Aim 2) use banked samples from 150 PLuSS participants to establish the association between 25(OH)D3 serum levels and inflammation and lung cancer risk biomarkers in sputum; (Aim 3) use murine models to quantify the effects of vitamin D3 status on NNK-induced lung carcinogenesis and cigarette smoke-induced pulmonary inflammation, and examine the impact of cigarette smoke exposure on 25(OH)D3 levels and expression of vitamin D3-metabolizing enzymes; and, (Aim 4) conduct a bioeffectiveness study of vitamin D3 supplementation in individuals at increased risk for lung cancer. We will evaluate whether supplementation corrects vitamin D3 deficiency and also investigate effects on inflammation and lung cancer risk biomarkers in sputum, circulating inflammation markers, and pulmonary function in this aim.