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

炎症、维生素 D 和结直肠癌风险和生存的生物标志物

• 批准号: 10320016
• 负责人: David Corley Gibbs
• 金额: $ 3.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-03 至 2022-06-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320016
• 关键词: Affect; Antineoplastic Agents; Binding Proteins; Biological; Biological Assay; Biological Markers; Biopsy; Blood; Calcifediol; Cancer Etiology; Cancer cell line; Cessation of life; Clinical Trials; Colon Carcinoma; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Controlled Clinical Trials; Data; Development; Double-Blind Method; Enzymes; Europe; Gene Proteins; Genes; Genetic Polymorphism; Genotype; Goals; Half-Life; Haplotypes; Heart Diseases; Human; IGFBP1 gene; Image Analysis; Immunohistochemistry; Incidence; Individual; Inflammation; Inflammatory; Inherited; Laboratory Study; Lesion; Linear Regressions; Link; Lipids; Logistic Regressions; Measurement; Measures; Metabolism; Modeling; Mucous Membrane; Nested Case-Control Study; Oxidoreductase; PTGS2 gene; Pathway interactions; Patients; Placebo Control; Placebos; Prospective cohort; Prospective cohort study; Prostaglandins; Protein Isoforms; Questionnaires; Randomized; Randomized Clinical Trials; Recommendation; Research; Risk; Source; United States; Variant; Vitamin D; Vitamin D supplementation; Vitamin D-Binding Protein; base; cancer survival; colon cancer risk; colorectal cancer risk; cyclooxygenase 2; follow-up; hazard; mortality; quantitative imaging; rectal; tissue biomarkers; treatment duration; tumor

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.

项目总结/摘要 结直肠癌（CRC）是美国癌症死亡的第二大原因。更高的循环 25-羟基维生素D3（25[OH]D3）的浓度，总维生素D暴露的最佳标志物，可能会降低 发展和死于CRC的风险超过50%。目前，没有公认的可修改（“可治疗”） CRC风险的生物标志物（类似于心脏病的脂质生物标志物）。然而，结果从我们的 以前的临床试验表明，维生素D补充剂可以有利地改变多个基因的表达， CRC风险的生物标志物（例如，p21、bax）表达。的表达 环氧合酶-2（考克斯-2）和15-前列腺素脱氢酶（15-PGDH）是炎症相关的关键酶， CRC风险的生物标志物，在癌细胞系中被维生素D有利地修饰，但维生素D的作用 在人体中补充考克斯-2和15-PGDH是未知的。此外，我们最近的研究结果表明， 表明25（OH）D3与结直肠腺瘤（结直肠腺瘤的直接前体）风险较低相关， 大多数CRCs）的不同之处在于常见的维生素D结合蛋白（DBP）同种型（由功能、遗传 多态性），影响循环DBP和25（OH）D3浓度和维生素D代谢。的 本课题的目的是研究维生素D对考克斯-2和15-PGDH的影响 正常结肠直肠粘膜中的表达，以及2）25（OH）D3和维生素D结合之间的相互作用 蛋白质（DBP）基因型/亚型与CRC风险和生存率的关系。我们假设：1）维生素D 补充有益地改变了外观正常的直肠粘膜中考克斯-2和15-PGDH的表达 和2）循环25（OH）D3浓度与CRC风险的相关性 和存活率因DBP亚型而异。对于目标1，我们将测量活检组织中考克斯-2和15-PDGH的表达 在一项随机临床试验中， 使用自动免疫组织化学和定量图像分析。我们将评估 补充维生素D（1，000 I.U./使用混合线性回归， 模型对于目标2，我们将汇总先前收集的问卷调查、维生素D测定和基因分型数据， 两项大型前瞻性队列研究，以研究DBP亚型是否改变25（OH）D3的相关性 在一项巢式病例对照研究中（n = 1，327例新发CRC病例，979例匹配 对照组），采用多变量logistic回归，并与CRC生存率在一项前瞻性队列研究（n = 1，327 CRC病例总数; 479例CRC特异性死亡）。这项研究将帮助 阐明维生素D的抗肿瘤作用，开发CRC风险的“可治疗”生物标志物， 以及根据遗传基因制定“个性化”维生素D建议， 最终降低CRC的发病率和死亡率。