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

• 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
• 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

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。胃肠道癌中TGFB/ELF，B-catenin和维生素D途径的交叉调节。人肝细胞癌和胃癌的特征是钙粘蛋白/catenin粘附和信号系统的改变。在某些情况下，这是在P-catenin和其他情况下激活突变的结果，E-钙粘着蛋白基因的失活或突变。这些遗传变化伴随的细胞信号传导和细胞粘附的改变可能有助于这些和其他前肢癌的致癌潜力。 TGFB/SMAD信号的缺陷在肝脏和肠道的癌症中也很常见。除了其“规范”效果外，TGFB/SMAD途径还可以与B-catenin/TCF转录机制相互作用，并合作地调节许多基因的转录。 ELF [+/-]和ELF [+/-]/SMACD4 [ - / - ]小鼠的表型，其中改变的TGFB信号伴随着E-Cadherin和B-catenin的变化，而B-catenin在人类疾病中首次将这两种途径联系起来，并为人类疾病的潜在共同基础提供了人类的潜在常见基础人类的发展。在我们的第一个目标中，我们将使用转基因动物模型，细胞系和外植体来研究B-蛋白信号传导在肝细胞，胃和胰腺癌中的作用，并确定其通过TGFB/SMAD信号传导其交叉调节的分子基础。我们将特别询问Wnt/Catenin信号传导的激活以及Wnt/Catenin调节的基因FGFBP是否需要ELF [+/-]和ELF [+/-]/smad4 [ - ] [ - - ]和Elf [+/-]和Elf [+/-]/smad3/smad3 [+/-]小鼠的肿瘤表型。在AIM 2中，我们将检验以下假设：维生素D途径为治疗HCC和GC提供了潜在的预防和治疗选择。初步数据表明，Wnt/B-catenin/TCF途径是维生素D及其类似物的癌症预防作用的关键中介。维生素D抑制B-catenin信号传导和B-catenin激活VDR。 Smads和B-catenin均可直接与维生素D受体（VDR）结合并增强其反式激活活性。维生素D及其类似物是几种不同肿瘤类型的生长的有效抑制剂，包括肝细胞和胃癌和维生素D，已在早期临床试验中用于治疗肝癌。在AIM 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-catenin特异性”维生素D类似物的活性，并在体外和VDR转基因动物中使用VDR敲低以检查维生素D受体的作用。涉及配体介导的VDR激活的治疗策略为抑制B-catenin信号传导和激活VDR的同时激活TGFB途径的潜在优势。这些数据将与120个冷冻的肝细胞癌和成对的对照组织中的活化B-catenin的表达以及改变TGFB/SMAD信号的标记有关。通过病理，临床和结果数据注释的该集合将提供前所未有的机会，将我们的转基因动物数据直接与人类材料进行比较。