Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
Winship Cancer Institute, Emory University, Atlanta, Georgia.
Cancer Prev Res (Phila). 2021 Jan;14(1):65-76. doi: 10.1158/1940-6207.CAPR-20-0140. Epub 2020 Sep 11.
Increased COX-2 and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 IU/day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically normal rectal mucosa from 62 paients with colorectal adenoma in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated IHC and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, because these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group ( = 0.001), 46% in the calcium group ( = 0.002), and 34% in the calcium + vitamin D group ( = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 ( rs4588*A), the COX-2/15-HPDG ratio decreased 70% ( = 0.0006), 75% ( = 0.0002), and 60% ( = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of patients with colorectal adenoma (perhaps especially those with the DBP2 isoform). PREVENTION RELEVANCE: Supplemental calcium and vitamin D reduce indicators of cancer-promoting inflammation in normal colorectal tissue in humans, thus furthering our understanding of how they may help prevent colorectal cancer.
COX-2 表达增加和 15-羟基前列腺素脱氢酶 (15-HPGD) 表达减少会促进前列腺素介导的炎症和结直肠癌变。实验研究表明，维生素 D 和钙可能会抑制这些途径，但它们对人类结直肠组织中 COX-2 和 15-HPGD 表达的影响尚不清楚。我们在一项安慰剂对照化学预防试验中，检测了补充维生素 D（每天 1000IU）和/或钙（每天 1200mg）对 62 例结直肠腺瘤患者形态正常直肠黏膜中 COX-2 和 15-HPGD 表达的影响。我们使用自动免疫组化和定量图像分析在基线和 1 年随访时测量生物标志物表达，并使用混合线性模型评估治疗效果。主要结果是 COX-2/15-HPGD 表达比值，因为这些酶作为生理拮抗剂发挥作用。治疗 1 年后，维生素 D 组全长隐窝中的 COX-2/15-HPGD 表达比值平均降低 47%（ = 0.001），钙组降低 46%（ = 0.002），钙+维生素 D 组降低 34%（ = 0.03），与安慰剂组相比。在具有功能性维生素 D 结合蛋白同工型 DBP2（rs4588*A）的个体中，与安慰剂相比，维生素 D、钙和联合补充组中的 COX-2/15-HPGD 比值分别降低 70%（ = 0.0006）、75%（ = 0.0002）和 60%（ = 0.006）。这些结果表明，维生素 D 和钙有利于调节 COX-2 和 15-HPGD 表达的平衡——这是与结直肠癌变密切相关的炎症生物标志物——在结直肠腺瘤患者的正常结直肠黏膜中（也许尤其是具有 DBP2 同工型的患者）。预防相关性：补充钙和维生素 D 可降低人类正常结直肠组织中促进癌症的炎症标志物，从而进一步了解它们如何帮助预防结直肠癌。
