Vitamin D & Calcium Regulation Biomarkers in Colon Cancer Risk Reduction

描述（由申请人提供）：本提案的长期目标是更好地了解钙和维生素D如何影响结直肠癌的发生。流行病学研究普遍支持钙、维生素D与结直肠癌风险呈负相关，尽管研究结果并不一致。在干预性腺瘤性息肉复发的研究中测试的饮食因素中，钙最一致地降低了风险。最近的证据进一步支持钙和维生素D的相互作用或附加作用。两个有趣的机制假设涉及维生素D自分泌/旁分泌活性和组织特异性钙敏感受体（CaSR）。钙和维生素D在体外和体内均具有抗增殖和促分化作用。维生素D的活性形式，1,25(OH)2D，是维生素D受体（VDR）的天然配体，它调节许多参与细胞周期控制的基因的表达。传统上认为，1,25(OH)2D合成仅受1，α (OH)酶（CYP27B1）对肾脏中25(OH)D（维生素D的储存形式）的作用调节。然而，1,25(OH)2D现在也被认为是直接在结肠组织中合成和降解，独立于肾脏1,25(OH)2D合成的通常触发因素。值得一提的是，关于启动组织特异性1,25(OH)2D合成（通过CYP27B1）和分解代谢（通过CYP24）的因素知之甚少。钙敏感受体（CaSR）被1,25(OH)2D上调，也被认为调节上皮分化。VDR表达受多种因素影响，可能改变钙和维生素D的预防效果。结肠组织中维生素D代谢酶或CaSR的表达是否对血浆维生素D浓度、饮食或非饮食因素有反应，以及VDR表达是否会改变维生素D或钙对结肠的作用，这些都是目前的研究方向。本研究使用一项正在进行的、随机、双盲、安慰剂对照的2x2因子试验（n=88）收集的数据和生物样本（血液和正常结肠组织的活检），研究钙和维生素D在散发性结直肠癌腺瘤患者中调节结直肠癌风险的生物标志物。使用自动定量免疫组织化学和图像分析，我们将测量CYP27B1和CYP24羟化酶的表达（分别作为组织特异性1,25(OH)2D合成和降解的测量），CaSR和VDR在正常出现的结直肠上皮中的表达，以研究钙或维生素D补充剂，血液中的维生素D代谢物或其他饮食和生活方式因素是否影响它们的表达。这项初步研究将提供功率计算所需的可变性估计，以便将这些研究问题应用于更大的、正在进行的干预试验。这项研究的结果需要进一步研究维生素D、钙和相关药物在预防结直肠癌方面的进展，结直肠癌是美国癌症死亡的第二大原因。

DESCRIPTION (provided by applicant): The long-term goals of this proposal are to better understand how calcium and vitamin D influence colorectal carcinogenesis. Epidemiological studies have generally supported an inverse association between calcium, vitamin D and risk of colorectal cancer, although findings have been inconsistent. Of dietary factors tested in intervention studies of adenomatous polyp recurrence, calcium has most consistently reduced risk. Recent evidence further supports either an interactive or additive role of calcium and vitamin D. Two intriguing mechanistic hypotheses concern vitamin D autocrine/paracrine activity and tissue-specific calcium sensing receptors (CaSR). Calcium and vitamin D exhibit anti-proliferative and pro-differentiation effects in vitro and in vivo. The active form of vitamin D, 1,25(OH)2D, is the natural ligand for the vitamin D receptor (VDR), which regulates expression of numerous genes involved in cell cycle control. Classically 1,25(OH)2D synthesis has been thought to be solely regulated by the action of 1,alpha(OH)ase (CYP27B1) on 25(OH)D (storage form of vitamin D) in the kidney. However, 1,25(OH)2D is now also known to be directly synthesized and degraded in colon tissue, independent of usual triggers of renal 1,25(OH)2D synthesis. Remarkably little is known about the factors that initiate tissue-specific 1,25(OH)2D synthesis (by CYP27B1) and catabolism (by CYP24). The calcium sensing receptor (CaSR) is upregulated by 1,25(OH)2D and is also thought to regulate epithelial differentiation. VDR expression, which is influenced by multiple factors, may modify the preventive efficacy of calcium and vitamin D. Whether expression of vitamin D metabolizing enzymes or CaSR in colon tissue responds to plasma vitamin D concentrations, diet, or non-dietary factors, and whether the effects of vitamin D or calcium on the colon is modified by VDR expression, is of current interest. This study uses data and biological samples (blood and biopsies of normal-appearing colorectal tissue) collected in an ongoing, randomized, double-blind, placebo-controlled 2x2 factorial pilot trial (n=88) of calcium and vitamin D in the modulation of biomarkers of risk for colorectal cancer in sporadic colorectal adenoma patients. Using automated quantitative immunohistochemistry with image analysis, we will measure the expression of CYP27B1 and CYP24 hydroxylases (as measures of tissue-specific 1,25(OH)2D synthesis and degradation, respectively), the CaSR, and the VDR in the normal-appearing colorectal epithelium to investigate whether calcium or vitamin D supplementation, vitamin D metabolites in the blood, or other diet and lifestyle factors influence their expression. This pilot study will provide the estimates of variability required for power calculations to apply these research questions to a larger, ongoing, intervention trial. The results of this study are needed for further progress in developing vitamin D, calcium and related agents in preventing colorectal cancer, the second leading cause of cancer deaths in the US.