Cross regulation of TGSB/elf, B-catenin and vitamin D pathways in Gastrointestin

胃肠道中 TGSB/elf、B-连环蛋白和维生素 D 途径的交叉调节

基本信息

批准号：
8744870
负责人：
RANDA A EL-ZEIN
金额：
$ 21.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/8744870
关键词：
Address Adhesions Adverse effects Affect Agonist Animal Model Animals Antibodies Apoptosis Binding Binding Proteins Cadherins Calcium Cell Adhesion Cell Line Cells Cholecalciferol Clinical Clinical Treatment Clinical Trials Collection Complex Consent Data Defect Development E-Cadherin Engineering Erinaceidae Etiology Exhibits Fibroblast Growth Factor Freezing Galactosidase Gene Targeting Genes Genetic Transcription Growth Hepatitis B Virus Hepatitis C virus Housing Human Human Development Hypercalcemia Hyperplasia In Vitro Intestines Knockout Mice Ligands Link Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of liver Malignant neoplasm of pancreas Measures Mediating Molecular Morphology Mus Mutation Nuclear Oncogenic Outcome Pathway interactions Phase II Clinical Trials Phenotype Phosphorylation Preventive Primary carcinoma of the liver cells Primitive foregut structure Property Proteins Regulation Reporter Role Signal Transduction Small Interfering RNA Specimen Sterols Stomach System TCF7L2 gene TGFB1 gene Testing Therapeutic Time Tissues Transactivation Transcriptional Regulation Transgenic Animals Tumor Cell Line Vitamin D Vitamin D Analog Vitamin D3 Receptor Work analog animal data base cancer prevention cancer therapy carcinogenesis cellular engineering dietary supplements feeding human disease inhibitor/antagonist intercellular communication knock-down malignant stomach neoplasm mammary epithelium neoplastic cell pancreatic neoplasm promoter repository research study small hairpin RNA small molecule smoothened signaling pathway tumor tumorigenic

项目摘要

Project 2. Cross regulation of TGFB/elf, B-catenin and vitamin D pathways in gastrointestinal cancers. Human hepatocellular carcinoma and gastric cancer are characterized by alterations in the cadherin/catenin adhesion and signaling system. In some situations this is a result of activating mutations in P-catenin and in others, inactivation or mutation of the E-cadherin gene. The alterations in cell signaling and cell adhesion that accompany these genetic changes likely contribute to the oncogenic potential of these and other foregut cancers. Defects in TGFB/smad signaling are also common in cancers of the liver and intestinal tract. In addition to its "canonical" effects the TGFB/smad pathway can also interact with the B-catenin/TCF transcriptional machinery and co-operatively regulate transcription of a number of genes. The phenotype of the elf[+/-] and elf[+/-]/smacd4[-/-]mice, in which altered TGFB signaling is accompanied by changes in E-cadherin and B-catenin links these two pathways for the first time in a human disease and provides important clues regarding a potential common basis for the development of human foregut cancers. In our first aim we will use transgenic animal models, cell lines and explants to investigate the role of B-catenin signaling in hepatocellular, gastric and pancreatic cancers and determine the molecular basis of its cross-regulation by TGFB/smad signaling. We will specifically ask if activation of wnt/catenin signaling and the wnt/catenin regulated gene FGFBP is required for the tumorigenic phenotype of the elf[+/-] and elf[+/-]/smad4[-/-] and elf[+/-] /smad3[+/-] mice. In aim 2 we will test the hypothesis that the vitamin D pathway provides a potential preventive and therapeutic option for the treatment of HCC and GC. Preliminary data demonstrates that the wnt/B-catenin/TCF pathway is a key intermediary in the cancer preventive action of vitamin D and its analogues. Vitamin D represses B-catenin signaling and B-catenin activates VDR. Both smads and B-catenin can bind directly to the vitamin D receptor (VDR) and potentiate its transactivation activity. Vitamin D and its analogues are potent repressers of the growth of several different tumor types including hepatocellular and gastric cancer and vitamin D is already in early clinical trials for the treatment of hepatocellular cancer. In aim 2 we will test the activity of vitamin D and of newly developed "B-catenin specific" vitamin D analogues in the animal models described above and use VDR knockdown in vitro and VDR transgenic animals to examine to role of the vitamin D receptor. A therapeutic strategy involving ligand-mediated activation of the VDR offers the potential benefit of repressing B-catenin signaling and activating the TGFB pathway at the same time as VDR is activated. These data will be linked to the expression of activated B-catenin and markers of altered TGFB/smad signaling in 120 frozen hepatocellular carcinomas and paired control tissues. This collection, annotated with pathological, clinical and outcome data will provide an unprecedented opportunity to compare our transgenic animal data directly with human material.

项目 2. 胃肠道癌症中 TGFB/elf、B-catenin 和维生素 D 通路的交叉调节。人肝细胞癌和胃癌的特征是钙粘蛋白/连环蛋白粘附和信号系统的改变。在某些情况下，这是 P-连环蛋白激活突变的结果，而在其他情况下，这是 E-钙粘蛋白基因失活或突变的结果。伴随这些基因变化的细胞信号传导和细胞粘附的改变可能导致这些和其他前肠癌的致癌潜力。 TGFB/smad 信号传导缺陷在肝癌和肠道癌中也很常见。除了其“典型”作用外，TGFB/smad 通路还可以与 B-连环蛋白/TCF 转录机制相互作用，并协同调节许多基因的转录。 elf[+/-] 和 elf[+/-]/smacd4[-/-] 小鼠的表型，其中 TGFB 信号传导的改变伴随着 E-钙粘蛋白和 B-连环蛋白的变化，首次将这两条途径联系起来人类疾病的时间，并提供有关人类前肠癌症发展的潜在共同基础的重要线索。我们的第一个目标是使用转基因动物模型、细胞系和外植体来研究 B-连环蛋白信号在肝细胞癌、胃癌和胰腺癌中的作用，并确定 TGFB/smad 信号传导交叉调节的分子基础。我们将特别询问 elf[+/-] 和 elf[+/-]/smad4[-/-] 和 elf[ 的致瘤表型是否需要激活 wnt/catenin 信号传导和 wnt/catenin 调节基因 FGFBP。 +/-] /smad3[+/-] 小鼠。在目标 2 中，我们将检验维生素 D 途径为 HCC 和 GC 的治疗提供潜在的预防和治疗选择的假设。初步数据表明，wnt/B-连环蛋白/TCF 途径是维生素 D 及其类似物预防癌症作用的关键中介。维生素 D 抑制 B-连环蛋白信号传导，而 B-连环蛋白激活 VDR。 Smad 和 B-连环蛋白都可以直接与维生素 D 受体 (VDR) 结合并增强其反式激活活性。维生素 D 及其类似物是多种不同肿瘤类型（包括肝细胞癌和胃癌）生长的有效抑制剂，维生素 D 已处于治疗肝细胞癌的早期临床试验中。在目标 2 中，我们将在上述动物模型中测试维生素 D 和新开发的“B-连环蛋白特异性”维生素 D 类似物的活性，并使用体外 VDR 敲低和 VDR 转基因动物来检查维生素 D 受体的作用。涉及配体介导的 VDR 激活的治疗策略提供了在 VDR 激活的同时抑制 B-连环蛋白信号传导和激活 TGFB 途径的潜在益处。这些数据将与 120 个冷冻肝细胞癌和配对对照组织中激活的 B-连环蛋白的表达和改变的 TGFB/smad 信号传导标记物相关。这个带有病理、临床和结果数据注释的集合将为我们的转基因动物数据直接与人类材料进行比较提供前所未有的机会。