CRD-BP-mediated regulation of Wnt signaling in intestinal tumorigenesis

CRD-BP 介导的 Wnt 信号在肠道肿瘤发生中的调节

• 批准号: 9076794
• 负责人: Vladimir S. Spiegelman
• 金额: $ 17.01万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9076794
• 关键词: Accounting; American Cancer Society; Animals; ApcMin/+ mice; Apoptotic; Binding; Biology; Cancer Etiology; Cell Cycle Progression; Cell Proliferation; Cell Size; Cells; Cessation of life; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Diagnosis; Down-Regulation; Doxycycline; Drug resistance; Epithelial; GLI gene; Gene Targeting; Genes; Goals; Health; Human; In Vitro; Inflammatory; Intestinal Neoplasms; Intestines; Knock-out; Lead; Ligands; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Methodology; Molecular; Morphologic artifacts; Mus; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Play; Prevention; Property; RNA; RNA-Binding Proteins; Regulation; Resistance; Role; Second Primary Cancers; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stem cells; Therapeutic; Transfection; Translations; Tumor Suppressor Genes; Up-Regulation; Validation; Woman; c-myc Genes; c-myc Proto-Oncogenes; cancer cell; cancer diagnosis; chemotherapeutic agent; chemotherapy; colon cancer cell line; colon carcinogenesis; colon tumorigenesis; design; gastrointestinal epithelium; in vivo; insight; intestinal epithelium; men; novel; pleiotropism; recombinase; response; self-renewal; smoothened signaling pathway; targeted treatment; tumor; tumorigenesis; tumorigenic; ubiquitin ligase; villin

DESCRIPTION (provided by applicant): Colorectal cancer is one of the most lethal of all cancers. One of the major drivers underlying the development of colorectal tumors is the Wnt/ß-catenin signaling pathway. We have previously established CRD-BP as a bona fide transcriptional target of Wnt signaling pathway and demonstrated that induction of CRD-BP is responsible for a variety of pleiotropic effects of Wnt/ß-catenin signaling in human colorectal cancer cells. We have demonstrated that: i) c-myc up-regulation by Wnt/ß-catenin signaling depends on CRD-BP; ii) CRD-BP facilitates cross-talk between Wnt and NF-κB pathways; iii) CRD-BP mediates activation of GLI1 transcriptional activity in response to Wnt signaling independently of Hh signaling pathway; iv) CRD-BP is transcriptionally regulated by c-myc and is involved in several functions of c-myc proto-oncogene, including regulation on translation, cell size, cell cycle progression, and cell proliferation; v) we have also uncovered a mechanism of CRD-BP-mediated stabilization of ßTrCP1 mRNA. We hypothesize that CRD-BP plays a central role in the modulation of Wnt/ß-catenin signaling in the oncogenic transformation of intestinal epithelia, including its role in the maintenance, self-renewal, differentiation, and transformation of intestinal epithelial stem cells (IESCs). We propose to study the mechanisms of CRD-BP involvement in intestinal tumorigenesis. Pursuant to these goals, our specific aims are: 1. To analyze the role of CRD-BP in the regulation of Wnt signaling in CRC cells. 2. To elucidate the mechanisms of CRD-BP function in intestinal tumorigenesis. Overall, the completion of the proposed studies will help elucidate the role of CRD-BP in colorectal carcinogenesis. It will also delineate the mechanisms of regulation and function of CRD-BP in these tumors. These studies may potentially lead to the design of agents capable of inhibiting CRD-BP that might be utilized in the therapy of CRC.

描述（由适用提供）：大肠癌是所有癌症中最致命的癌症之一。彩色肿瘤发展的主要驱动因素之一是Wnt/ß-catenin信号通路。我们以前已经将CRD-BP建立为Wnt信号通路的真正转录靶标，并证明CRD-BP的诱导是造成Wnt/ß-catenin信号在人类结直肠癌细胞中的多种多效性效应。我们已经证明：i）Wnt/ß-catenin信号通过Wnt/ß-catenin信号上调取决于CRD-BP； ii）CRD-BP支持Wnt和NF-κB路径之间的串扰； iii）CRD-BP介导Gli1转录活性的激活，响应于HH信号通路独立于Wnt信号； iv）CRD-BP在转录上受C-Myc调节，并参与了C-Myc原始癌的多种功能，包括对翻译的调节，细胞的调节 大小，细胞周期进程和细胞增殖； v）我们还发现了CRD-BP介导的βTrCP1mRNA稳定的机制。我们假设CRD-BP在Wnt/ß-catenin信号传导的调节中起着核心作用 肠上皮干细胞（IESC）。我们建议研究CRD-BP参与肠道肿瘤发生的机制。根据这些目标，我们的具体目的是：1。分析CRD-BP在CRC细胞中Wnt信号传导调节中的作用。 2。阐明CRD-BP功能在肠道肿瘤发生中的机制。总体而言，提出的研究的完成将有助于阐明CRD-BP在结直肠癌发生中的作用。它还将描述这些肿瘤中CRD-BP调节和功能的机理。这些研究可能会导致设计能够抑制CRD-BP的药物的设计，而CRD BP可能用于CRC治疗。