A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients.
A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients.
复制标题
DOI：
10.1158/1940-6207.capr-12-0292
复制
发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Bostick RM
中科院分区：
文献类型：
--
作者：
Ahearn TU;Shaukat A;Flanders WD;Rutherford RE;Bostick RM
APC/β-Catenin通路紊乱是结直肠癌发生的常见早期事件，在基础科学研究中受钙和维生素D的影响。为了评价钙和维生素D对散发性结直肠腺瘤患者正常大肠黏膜中APC、β-连环蛋白和E-钙粘蛋白表达的影响，我们进行了一项随机、双盲、安慰剂对照的2×2因素临床试验。病理证实的结直肠腺瘤患者接受2g/天的元素钙和/或800IU/天的维生素D3治疗，与安慰剂治疗6个月(N=92；23个/组)。用标准化的自动化免疫组织化学方法检测正常直肠黏膜活检组织中APC、β-连环蛋白和E-钙粘蛋白在结肠隐窝中的表达和分布，并用图像分析进行定量。与安慰剂组相比，补充维生素D3组隐窝上部40%的APC比例(ϕh APC)增加2 1%(P=0.0 1)，β-连环蛋白减少12%(P=0.18)，E-钙粘素增加72%(P=0.0 3)，ϕh APC/β-连环蛋白比值(βh APC/APC-连环蛋白评分)增加31%(P=0.0 2)。补钙组ϕhAPC增加10%(p=0.12)，β-catenin降低15%(p=0.0 8)，APC/β-catenin增加41%(p=0.0 1)。补钙/维生素D3组β-catenin下降11%(p=0.2)，E-cad上升51%(p=0.08)，β/apc-catenin评分增加16%(p=0.26)。这些结果支持1)钙和维生素D改变人类的APC、β-连环蛋白和E-钙粘附素的表达，以降低结直肠癌的风险；2)钙和维生素D作为预防结直肠癌的潜在化学预防药物；以及3)APC、β-连环蛋白和E-钙粘连蛋白的表达作为结直肠肿瘤的可改变的、癌前风险生物标志物的可能性。
APC/β-catenin pathway perturbation is a common early event in colorectal carcinogenesis and is affected by calcium and vitamin D in basic science studies. To assess the effects of calcium and vitamin D on APC, β-catenin, and E-cadherin expression in the normal appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Pathology-confirmed colorectal adenoma cases were treated with 2 g/day elemental calcium and/or 800 IU/day vitamin D3 versus placebo over 6 months (N=92; 23/group). Overall APC, β-catenin, and E-cadherin expression and distributions in colon crypts in normal-appearing rectal mucosa biopsies were detected by standardized automated immunohistochemistry and quantified by image analysis. In the vitamin D3-supplemented group relative to placebo, the proportion of APC in the upper 40% of crypts (ϕh APC) increased 21% (p=0.01), β-catenin decreased 12% (p=0.18), E-cadherin increased 72% (p=0.03), and the ϕh APC/β-catenin ratio (APC/β-catenin score) increased 31% (p=0.02). In the calcium-supplemented group ϕh APC increased 10% (p=0.12), β-catenin decreased 15% (p=0.08), and the APC/β-catenin score increased 41% (p=0.01). In the calcium/vitamin D3 supplemented group β-catenin decreased 11% (p=0.20), E-cadherin increased 51% (p=0.08), and the APC/β-catenin score increased 16% (p=0.26). These results support 1) that calcium and vitamin D modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms, 2) calcium and vitamin D as potential chemopreventive agents against colorectal neoplasms, and 3) the potential of APC, β-catenin, and E-cadherin expression as modifiable, pre-neoplastic risk biomarkers for colorectal neoplasms.