Beta-catenin-specific regulation of the vitamin D pathway in colon cancer

结肠癌中维生素 D 通路的 β-连环蛋白特异性调节

• 批准号: 8212392
• 负责人: STEPHEN W BYERS
• 金额: $ 30.9万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-04 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212392
• 关键词: AF2; Ablation; Adenomatous Polyposis Coli; Adverse effects; Affect; Agonist; Alleles; Animal Feed; Animal Model; Animals; Azoxymethane; Binding; Biological Assay; Calcium; Cancer Etiology; Cells; Cessation of life; Chemopreventive Agent; Cholecalciferol; Colon Carcinoma; Colorectal Cancer; Computer Simulation; Data; Development; Diet; Dietary intake; Epidemiologic Studies; Epithelium; Exhibits; Familial hypophosphatemic bone disease; Family; Genes; Goals; Growth; Health; Human; Hyperplasia; Incidence; Inherited; Intestinal Cancer; Intestinal Neoplasms; Intestines; Knockout Mice; Lead; Libraries; Ligands; Malignant Neoplasms; Mediating; Mus; Mutation; Neoplasms; Nuclear; Nuclear Receptors; Oncogenic; Pathway interactions; Patients; Phenotype; Play; Point Mutation; Predisposition; Preventive; Principal Investigator; Property; Regimen; Regulation; Reporter; Resistance; Role; Screening procedure; Series; Side; Signal Transduction; Specific qualifier value; Specificity; Structural Models; Sunlight; Testing; Therapeutic; Time; Transactivation; Transgenic Animals; Transgenic Mice; United States; Vitamin D; Vitamin D Analog; Vitamin D Response Element; Work; analog; beta catenin; biochemical model; cancer cell; dietary supplements; epidemiological model; feeding; in vivo; inhibitor/antagonist; malignant colon tumor; model development; mutant; programs; promoter; simulation; small molecule libraries; therapy development; thyroid hormone receptor associated protein 220; tumor; tumorigenesis; virtual; vitamin therapy; yeast two hybrid system

DESCRIPTION (provided by applicant): Epidemiological studies show a relationship between the dietary intake or UV-activation of pre-vitamin D and the incidence of colon cancers. This relationship indicates that vitamin D may have a chemopreventive action and animal studies have confirmed the preventive efficacy of vitamin D and its analogues in colon cancer. However in many instances human cancer cells and tumors become resistant to treatment. Another major concern is the high incidence of side effects unrelated to the anti cancer actions of vitamin D. Even though both the cancer- and non-cancer-related actions of vitamin D are mediated via interaction with its nuclear receptor (VDR) it is not clear if they can be separated. Studies that elucidate the precise mechanism(s) whereby vitamin D exerts its anti-cancer effects are of great significance. A detailed understanding of these pathways may lead to the development of agents or dietary regimens that are effective in patients that are resistant to vitamin therapy and/or to the development of treatments with fewer side effects. Preliminary data demonstrates that the wnt/2- catenin/TCF oncogenic pathway, almost universally activated in colon cancer, is a key intermediary in the preventive action of vitamin D and its analogues in colon cancer. Our data shows that vitamin D represses 2-catenin signaling and that 2-catenin activates VDR. Importantly, we find that certain VDR mutants and vitamin D analogues allow interaction with 2-catenin but not other co-activators. This proposal seeks to explore and exploit the concept that the vitamin D pathway can be selectively activated in intestinal cancer cells expressing high levels of activated 2-catenin. Such a strategy would offer the additional benefit of repressing 2-catenin signaling at the same time as VDR is activated. In aim one we propose a series of computational, structural, and mutational analyses to identify structural features of the VDR, which specify its interaction with 2-catenin. In aim two we will screen virtual and real libraries to identify ligands which allow 2-catenin but not other co-activators to bind the VDR. Our goal is to develop vitamin D analogues that can activate VDR only in situations, such as colon cancer, in which 2-catenin is elevated. In aim three we will use transgenic animals to investigate the role of VDR, VDR mutants and 2- catenin specific vitamin D analogues in protection from 2-catenin induced neoplasia. The APC1638 mouse develops spontaneous intestinal cancers and we recently generated APC1638/VDR-/- bigenic animals. We will use APC1638 ,APC1638/VDR-/-, VDR-mutant and azoxymethane treated animals to investigate the ability of vitamin D analogues to support VDR/2-catenin interactions and whether ablation of VDR plays any role in intestinal tumor development. PUBLIC HEALTH RELEVANCE: Colorectal cancer is the second leading cause of cancer-related death in the United States. The development of virtually all colorectal cancer results from mutation in adenomatous polyposis coli (APC) or 2-catenin genes. A wealth of epidemiological and animal model data supports the hypothesis that vitamin D and its analogues (and sunlight) are potent inhibitors of CRC and our own work shows that certain analogues of vitamin D can inhibit the growth of CRC in a 2-catenin-specific manner. We now propose a series of computational, biochemical and animal model studies to explore and exploit the concept that the vitamin D pathway can be preferentially activated in colon cancers which express high levels of activated 2-catenin.

描述（由申请人提供）： 流行病学研究表明，饮食摄入量或紫外线激活前体Vitamin D与结肠癌的发生率之间的关系。这种关系表明，维生素D可能具有化学预防作用，动物研究证实了维生素D及其在结肠癌中的预防效果。但是，在许多情况下，人类癌细胞和肿瘤对治疗具有抗药性。另一个主要问题是，副作用的高发病率与维生素D的抗癌作用无关。尽管维生素D的癌症和非癌症相关作用均通过与其核受体（VDR）的相互作用进行介导，但尚不清楚它们是否可以分离。阐明维生素D造成其抗癌作用的精确机制的研究具有重要意义。对这些途径的详细理解可能会导致对耐维生素治疗和/或开发具有较少副作用的治疗的患者有效的药物或饮食方案的发展。初步数据表明，在结肠癌中几乎普遍激活的Wnt/2- Catenin/TCF致癌途径是维生素D及其在结肠癌中类似物的预防作用中的关键中介。我们的数据表明，维生素D抑制2-catenin信号，而2-catenin激活VDR。重要的是，我们发现某些VDR突变体和维生素D类似物允许与2-catenin相互作用，但不能与其他共激活剂相互作用。该提案旨在探索和利用以下概念：维生素D途径可以在表达高水平活化的2-catenin的肠道癌细胞中选择性激活。这种策略将在激活VDR的同时抑制2-catenin信号的额外好处。在AIM ONE中，我们提出了一系列计算，结构和突变分析，以识别VDR的结构特征，该特征指定了其与2-catenin的相互作用。在目标两个中，我们将筛选虚拟和真实库，以识别允许2-catenin但不能绑定VDR的配体。我们的目标是开发只能在结肠癌等情况下激活VDR的维生素D类似物，其中2-catenin升高。在AIM三中，我们将使用转基因动物研究VDR，VDR突变体和2- catenin特异性维生素D类似物在2-Catenin诱导的肿瘤中的保护中的作用。 APC1638小鼠会产生自发的肠癌，我们最近生成了APC1638/VDR - / - 胆汁胆汁动物。我们将使用APC1638，APC1638/VDR - / - ，VDR-突变剂和偶氮甲烷处理的动物研究维生素D类似物支持VDR/2-catenin相互作用的能力，以及VDR在肠道肿瘤发展中的作用是否扮演任何作用。公共卫生相关性：大肠癌是美国与癌症相关死亡的第二大原因。几乎所有结直肠癌的发展是由腺瘤性息肉病（APC）或2-catenin基因突变引起的。大量的流行病学和动物模型数据支持以下假设：维生素D及其类似物（和阳光）是CRC的有效抑制剂，我们自己的工作表明，维生素D的某些类似物可以以2-Catenin特异性方式抑制CRC的生长。现在，我们提出了一系列计算，生化和动物模型研究，以探索和利用这样的概念，即在表达高水平活化的2-catenin的高水平的结肠癌中，维生素D途径可以优先激活。

项目成果

Control of TCF-4 expression by VDR and vitamin D in the mouse mammary gland and colorectal cancer cell lines.

• DOI: 10.1371/journal.pone.0007872
• 发表时间: 2009-11-17
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Beildeck ME;Islam M;Shah S;Welsh J;Byers SW
• 通讯作者: Byers SW

Putative biomarkers and targets of estrogen receptor negative human breast cancer.

• DOI: 10.3390/ijms12074504
• 发表时间: 2011
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Sahab ZJ;Man YG;Byers SW;Sang QX
• 通讯作者: Sang QX

Alteration in protein expression in estrogen receptor alpha-negative human breast cancer tissues indicates a malignant and metastatic phenotype.

• DOI: 10.1007/s10585-010-9338-8
• 发表时间: 2010-10
• 期刊: CLINICAL & EXPERIMENTAL METASTASIS
• 影响因子: 4
• 作者: Sahab, Ziad J.;Man, Yan-Gao;Semaan, Suzan M.;Newcomer, Robert G.;Byers, Stephen W.;Sang, Qing-Xiang Amy
• 通讯作者: Sang, Qing-Xiang Amy

Cooperation between BRCA1 and vitamin D is critical for histone acetylation of the p21waf1 promoter and growth inhibition of breast cancer cells and cancer stem-like cells.

• DOI: 10.18632/oncotarget.2582
• 发表时间: 2014-12-15
• 期刊: Oncotarget
• 作者: Pickholtz I;Saadyan S;Keshet GI;Wang VS;Cohen R;Bouwman P;Jonkers J;Byers SW;Papa MZ;Yarden RI
• 通讯作者: Yarden RI

Non-receptor tyrosine kinase 2 reaches its lowest expression levels in human breast cancer during regional nodal metastasis.

非受体酪氨酸激酶 2 在人类乳腺癌区域淋巴结转移期间达到最低表达水平。

• DOI: 10.1007/s10585-011-9437-1
• 发表时间: 2012
• 期刊: Clinical & experimental metastasis
• 影响因子: 4
• 作者: Sang,Qing-XiangAmy;Man,Yan-Gao;Sung,YouMe;Khamis,ZahraaI;Zhang,Lihua;Lee,Mi-Hye;Byers,StephenW;Sahab,ZiadJ
• 通讯作者: Sahab,ZiadJ