Biomarkers of Inflammation, Vitamin D, and Colorectal Cancer Risk and Survival

项目摘要/摘要 结直肠癌(CRC)是美国癌症死亡的第二大原因。更高的发行量 25-羟基维生素D3(25[OH]D3)是总维生素D暴露的最佳标志，其浓度可能会降低 罹患结直肠癌并死于结直肠癌的风险超过50%。目前，没有公认的可修改(可治疗) 结直肠癌风险的生物标记物(类似于心脏病的脂质生物标记物)。然而，我们的结果是 先前的临床试验表明，补充维生素D可以有利地改变多个 正常大肠粘膜中大肠癌风险的生物标记物(如p21、bax)。的表达方式 环氧合酶-2(COX-2)和15-前列腺素脱氢酶(15-PGDH)是炎症相关的关键酶 癌细胞系中维生素D有利地修饰的CRC风险的生物标志物，但维生素D的作用 人类对COX-2和15-PGDH的补充尚不清楚。此外，我们最近的研究结果 表明25(OH)D3与较低的结直肠腺瘤风险(直肠癌的直接先兆)有关 大多数CRC)不同于常见的维生素D结合蛋白(DBP)亚型(由功能、遗传因素决定 影响循环中DBP和25(OH)D3浓度和维生素D代谢的基因。这个 这个项目的目标是调查未知的：1)维生素D对COX-2和15-PGDH的影响 2)25(OH)D3与维生素D结合的相互作用 蛋白质(DBP)基因型别/异构体与结直肠癌风险和生存率的关系。我们假设：1)维生素D 补充剂有利于改善正常直肠黏膜中COX-2和15-PGDH的表达 2)循环中25(OH)D3浓度与结直肠癌风险的关系 DBP亚型不同，存活率也不同。对于目标1，我们将检测活检组织中COX-2和15-PDGH的表达 在一项随机临床试验中，对104例结直肠腺瘤患者的外观正常的直肠粘膜进行了研究。 使用自动免疫组织化学和定量图像分析。我们将评估 用混合线性回归法研究维生素D补充(1,000国际单位/天)一年对两个生物标志物的影响 模特们。对于目标2，我们将汇集之前收集的问卷、维生素D检测和基因分型数据 两项大型前瞻性队列研究，以调查DBP亚型是否改变25(OH)D3的关联性 嵌套式病例对照研究中浓度与结直肠癌风险的关系(n=1,327例发生结直肠癌病例，979例匹配 对照)，使用多变量Logistic回归，并与前瞻性队列研究中的结直肠癌生存率(n=1,327 总的结直肠癌病例；479例结直肠癌特定死亡)使用COX比例风险回归。这项研究将会有所帮助 阐明维生素D的抗肿瘤作用，结直肠癌风险的可治疗生物标记物的发展， 以及根据一个人的遗传基因类型，制定“个性化的”维生素D推荐标准。 最终降低结直肠癌发病率和死亡率。

Project Summary / Abstract Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Higher circulating concentrations of 25-hydroxyvitamin D3 (25[OH]D3), the best marker of total vitamin D exposure, may lower the risk of developing and dying from CRC by over 50%. Currently, there are no accepted modifiable (‘treatable’) biomarkers of risk for CRC (analogous to lipid biomarkers for heart disease). However, results from our previous clinical trials indicate that vitamin D supplementation can favorably modify the expression of multiple biomarkers of risk for CRC (e.g., p21, bax) in the normal colorectal mucosa. The expression of cyclooxygenase-2 (COX-2) and 15-prostaglandin dehydrogenase (15-PGDH) are key inflammation-related biomarkers of CRC risk that are favorably modified by vitamin D in cancer cell lines, but the effects of vitamin D supplementation on COX-2 and 15-PGDH in humans are unknown. Additionally, results from our recent study indicate that the association of 25(OH)D3 with lower risk of colorectal adenoma (the immediate precursor to most CRCs) differs by common vitamin D binding protein (DBP) isoforms (determined by functional, genetic polymorphisms) that affect circulating DBP and 25(OH)D3 concentrations and vitamin D metabolism. The goals of this project are to investigate the unknown: 1) effects of vitamin D on COX-2 and 15-PGDH expression in the normal colorectal mucosa, and 2) interactions between 25(OH)D3 and vitamin D binding protein (DBP) genotypes/isoforms in relation to CRC risk and survival. We hypothesize that: 1) vitamin D supplementation favorably modifies COX-2 and 15-PGDH expression in the normal-appearing rectal mucosa of colorectal adenoma patients, and 2) the associations of circulating 25(OH)D3 concentrations with CRC risk and survival differ by DBP isoform. For Aim 1, we will measure COX-2 and 15-PDGH expression in biopsies of the normal-appearing rectal mucosa of colorectal adenoma patients (n = 104) in a randomized clinical trial, using automated immunohistochemistry and quantitative image analysis. We will estimate the effects of vitamin D supplementation (1,000 I.U./day) over one year on the two biomarkers using mixed linear regression models. For Aim 2, we will pool previously collected questionnaire, vitamin D assay, and genotyping data from two large prospective cohort studies to investigate whether DBP isoforms modify the association of 25(OH)D3 concentrations with CRC risk in a nested case-control study (n = 1,327 incident CRC cases, 979 matched controls) using multivariable logistic regression, and with CRC survival in a prospective cohort study (n = 1,327 total CRC cases; 479 CRC-specific deaths) using Cox-proportional hazards regression. This research will help elucidate the anti-neoplastic effects of vitamin D, the development of ‘treatable’ biomarkers of risk for CRC, and the development of ‘personalized’ vitamin D recommendations, based on one’s inherited genotypes, ultimately reducing CRC incidence and mortality.