(PQA1) Mechanism of Vitamin D Chemoprevention Against Colon Cancer

(PQA1) 维生素 D 化学预防结肠癌的机制

• 批准号: 8912882
• 负责人: Yan Chun LI
• 金额: $ 43.04万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912882
• 关键词: 25-hydroxyvitamin D; Address; Affect; Attention; Azoxymethane; Bacteria; Bile Acid Biosynthesis Pathway; Bile Acids; Cancer Etiology; Cancer Model; Catabolism; Cessation of life; Chemoprevention; Chemopreventive Agent; Cholic Acids; Clostridium; Colon; Colon Carcinoma; Complex; Data; Diet; Dihydroxycholecalciferols; Disease; Epidemiologic Studies; Epithelial; Fatty acid glycerol esters; Fibroblasts; Genetically Engineered Mouse; Gnotobiotic; Goals; Growth; Health; Hepatic; Hormones; Human; Incidence; Intestines; Kidney; Lactobacillus acidophilus; Ligands; Lithocholic Acid; Maintenance; Malignant Neoplasms; Metabolism; Microbe; Mixed Function Oxygenases; Modeling; Molecular; Mono-S; Mus; Nuclear Receptors; Osteoporosis; Pharmaceutical Preparations; Physiological; Production; Randomized Clinical Trials; Receptor Signaling; Regulation; Risk; Risk Factors; Role; Skin; Small Intestines; Supplementation; Testing; Transgenic Mice; Tumor Burden; Tumor Promotion; Vitamin D; Vitamin D3 Receptor; Wild Type Mouse; absorption; antimicrobial peptide; bile acid transporter; bone health; dietary supplements; feeding; microbial; microbial host; mortality; prevent; promoter; public health relevance; tumor; tumorigenesis; western diet

DESCRIPTION (provided by applicant): The goal of this application is to address RFA-CA-12-015 PQA1: What is the molecular mechanism by which a drug that is chronically used for other indications protects against cancer incidence and mortality? Vitamin D (VD) is a widely and chronically used supplement for maintenance of bone health and for treatment of osteoporosis, but a growing body of evidence has indicated that VD has potent chemopreventive effects against colon cancer by unknown mechanisms. Thus the central question to be addressed is: What is the molecular mechanism by which Vitamin D prevents colon cancer? Colon cancer is a leading cause of cancer- related deaths in the US. Low VD status is associated with increased colon cancer incidence, chemopreventive effects of VD have been demonstrated in colon cancer models, and large randomized clinical trials are being conducted to evaluate VD's chemopreventive efficacy against colon cancer in humans, but the mechanism underlying VD's anti-colon cancer activity remains to be defined. Secondary bile acids (BA) are potent colon cancer promoters. VD is known to affect colonic secondary BA levels by regulating host and colonic bacterial BA metabolism. Therefore we hypothesize that VD regulation of secondary BA levels is a key molecular mechanism underlying VD's chemopreventive activity against colon cancer. Moreover, the tumor-promoting secondary BA lithocholic acid (LCA) can also activate the vitamin D receptor (VDR), and LCA-VDR signals, like VD-VDR signals, also promote secondary BA catabolism by inducing Cyp3A, which can paradoxically limit LCA's tumor-promoting effects. Therefore we also hypothesize that VDR signals activated by VD or LCA limit secondary BA levels, thus mitigating tumor promotion by BAs. We will test these hypotheses using colon cancer models in genetically engineered mice with altered vitamin D hormone or VDR levels, and in gnotobiotic mice with altered bacterial secondary BA production. In Aim 1 we will determine the VDR-dependent host and microbe mechanisms that regulate Western diet-induced secondary BAs and colonic tumorigenesis. We will assess secondary BA levels and colonic tumorigenesis in WT, VDR(-/-) and transgenic mice over-expressing epithelial VDR that are fed Western diet or VD supplemented diet. In Aim 2 we will dissect the role of VD- independent LCA-VDR signals in colonic tumorigenesis. We will compare effects of Western diet or dietary LCA on secondary BAs and colonic tumorigenesis in WT, VDR(-/-), Cyp27b1(-/-) and VDR(-/-)/Cyp27b1(-/-) mice. Cyp27b1(-/-) and VDR(-/-)/Cyp27b1(-/-) mice cannot synthesize VD hormone, allowing us to dissect the chemopreventive effects of LCA-VDR signals without confounding effects of endogenous VD hormone. In Aim 3 we will assess the role of microbial 7¿-dehydroxylase (7-DH) in VD chemoprevention. We will compare tumorigenesis in gnotobiotic mice mono-associated with Lactobacillus acidophilus lacking 7-DH to mice also associated with Clostridium scindens expressing 7-DH fed Western diet or diet supplemented with VD. These studies will greatly advance our understanding of chemopreventive mechanisms of VD against colon cancer.

描述（由申请人提供）：本申请的目的是解决RFA-CA-12-015 PQA 1：长期用于其他适应症的药物预防癌症发病率和死亡率的分子机制是什么？维生素D（VD）是一种广泛和长期使用的补充剂，用于维持骨骼健康和治疗骨质疏松症，但越来越多的证据表明，VD通过未知的机制对结肠癌具有有效的化学预防作用。因此，需要解决的中心问题是：维生素D预防结肠癌的分子机制是什么？结肠癌是美国癌症相关死亡的主要原因。低VD状态与结肠癌发病率增加相关，VD的化学预防作用已在结肠癌模型中得到证实，正在进行大型随机临床试验以评估VD对人类结肠癌的化学预防功效，但VD抗结肠癌活性的机制仍有待确定。次级胆汁酸（BA）是有效的结肠癌促进剂。已知VD通过调节宿主和结肠细菌BA代谢来影响结肠次级BA水平。因此，我们假设VD调节继发性BA水平是VD对结肠癌化学预防活性的关键分子机制。此外，促肿瘤的二级BA石胆酸（LCA）也可以激活维生素D受体（VDR），并且LCA-VDR信号与VD-VDR信号一样，也通过诱导Cyp 3A而促进二级BA催化，这可能矛盾地限制LCA的促肿瘤作用。因此，我们还假设VD或LCA激活的VDR信号限制了继发性BA水平，从而减轻了BA的肿瘤促进作用。我们将在维生素D激素或VDR水平改变的基因工程小鼠和细菌次生BA产生改变的gnotobiotic小鼠中使用结肠癌模型来测试这些假设。在目的1中，我们将确定VDR依赖性宿主和微生物调节西方饮食诱导的继发性BA和结肠肿瘤发生的机制。我们将评估喂食西方饮食或VD补充饮食的WT、VDR（-/-）和过度表达上皮VDR的转基因小鼠中的继发性BA水平和结肠肿瘤发生。在目的2中，我们将剖析VD非依赖性LCA-VDR信号在结肠肿瘤发生中的作用。我们将比较西方饮食或饮食LCA对WT、VDR（-/-）、Cyp 27 b1（-/-）和VDR（-/-）/Cyp 27 b1（-/-）小鼠中继发性BA和结肠肿瘤发生的影响。Cyp 27 b1（-/-）和VDR（-/-）/Cyp 27 b1（-/-）小鼠不能合成VD激素，这使我们能够在没有内源性VD激素混杂作用的情况下分析LCA-VDR信号的化学预防作用。在目标3中，我们将评估微生物7-脱羟酶（7-DH）在VD化学预防中的作用。我们将比较与缺乏7-DH的嗜酸乳杆菌单相关的无菌小鼠与也与表达7-DH的梭菌相关的喂食西方饮食或补充有VD的饮食的小鼠中的肿瘤发生。这些研究将极大地推进我们对VD对结肠癌的化学预防机制的理解。