Mechanisms of suppression of colon cancer by receptor tyrosine phosphatase PTPRT

受体酪氨酸磷酸酶PTPRT抑制结肠癌的机制

基本信息

批准号：
8125027
负责人：
Zhenghe Wang
金额：
$ 28.47万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-28 至 2013-07-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8125027
关键词：
Affect Alleles Apoptosis Base Sequence Binding Cancer Patient Cancer cell line Cell Adhesion Cell Adhesion Molecules Cell-Cell Adhesion Colon Carcinoma Colorectal Cancer Cultured Cells DNA Development Dimerization Disseminated Malignant Neoplasm Epithelial Extracellular Domain Future Genes Goals Grant Growth Homologous Gene Homologous Protein In Vitro Knock-in Mouse Laboratories Lead Malignant Neoplasms Mediating Mediator of activation protein Mutagenesis Mutate Mutation Neoplasm Metastasis Nuclear Translocation Nude Mice Oncogenic PTPRT gene Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Protein Tyrosine Phosphatase Gene Proteomics Regulation Research Role Signal Pathway Signal Transduction Small Interfering RNA Stat3 protein Structure Testing Therapeutic Transgenic Mice Tumor Cell Invasion Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Derived Tyrosine Phosphorylation Work Xenograft Model Xenograft procedure base cancer cell cancer genomics design extracellular human PTPRT protein in vivo innovation knock-down mutant neoplastic cell novel strategies pre-clinical receptor research study sarcoma tumor tumor growth tumor progression tumorigenesis upstream kinase

项目摘要

DESCRIPTION (provided by applicant): The long term goal of this grant is to elucidate the mechanism through which mutations of receptor protein tyrosine phosphatase PTPRT lead to the development of colorectal cancers. This proposal tests the hypothesis that mutations of PTPRT impair critical tumor suppression functions leading to accelerated tumor growth and/or tumor progression through disrupting cell-cell adhesion and that `signal transducer and activator of transcription 3' (STAT3) plays critical roles in PTPRT regulated tumor suppressor signaling pathways. The first aim of this proposal will investigate whether tumor specific mutations of PTPRT impair growth inhibitory functions in culture cells and in athymic nude mice xenograft models. The second aim will determine whether STAT3 acts as the critical mediator of PTPRT regulated cell signaling pathway that is important in tumor development. The third aim will determine whether tumor-derived mutations in the extracellular domain of PTPRT affect cell-cell adhesion. This proposal builds upon our successful exploitation of a cancer genomic approach that systematically explored the potential roles of protein tyrosine phosphatases in the development of colorectal cancer. Our initial study identified six tyrosine phosphatase genes that are mutated in 26% of colorectal cancers, providing compelling evidence that tyrosine phosphatases play critical roles in the development of colorectal cancers. PTPRT is the most frequently mutated tyrosine phosphatase gene among the six genes and over-expression of PTPRT inhibits growth of colorectal cancer cells. Recent work in this laboratory has now shown that the extracellular domain of PTPRT mediates homophilic binding, suggesting that PTPRT, like its close homologues, may also mediate cell-cell adhesion and thus play a critical role in tumor progression, given the fact that many metastatic cancers lose their cell adhesion properties. Using an innovative proteomic approach, we also identified STAT3, which is consistently activated in many cancers, as a PTPRT substrate. These observations emphasize the importance of determining whether STAT3 is a critical mediator of PTPRT tumor suppressor signaling and how tumor specific mutations affect tumor growth and cell-cell adhesion. Relevance: The proposed study will expand our understanding of new factors that cause colon cancer. This focus on new targets underlying colon cancer should facilitate design of novel approaches to treatment of cancer patients.

描述（由申请人提供）：该赠款的长期目标是阐明受体蛋白酪氨酸磷酸酶PTPRT突变导致结直肠癌的发展的机制。该提案检验了以下假设：PTPRT的突变损害了关键的肿瘤抑制功能，导致肿瘤生长和/或肿瘤进展通过破坏细胞细胞粘附，并且“转录3'（STAT3）的激活剂（STAT3）在PTPRT调节的肿瘤抑制肿瘤抑制信号信号通路中起关键作用。该提案的第一个目的是研究PTPRT的肿瘤特异性突变是否会损害培养细胞和无胸腺裸鼠异种移植模型中的生长抑制作用。第二个目标将确定STAT3是否充当PTPRT调节细胞信号通路的关键介体，这对肿瘤发育很重要。第三个目标将决定PTPRT细胞外域中肿瘤衍生的突变是否影响细胞 - 细胞粘附。该提案以我们成功剥削癌症基因组方法为基础，该方法系统地探讨了蛋白质酪氨酸磷酸酶在结直肠癌发展中的潜在作用。我们的初步研究确定了六个酪氨酸磷酸酶基因，它们在26％的结直肠癌中突变，提供了令人信服的证据，表明酪氨酸磷酸酶在结直肠癌的发展中起着关键作用。 PTPRT是六个基因中最常见的酪氨酸磷酸酶基因，PTPRT的过表达抑制了结直肠癌细胞的生长。该实验室的最新工作现已表明，PTPRT的细胞外结构域介导同粒细胞结合，表明PTPRT与其紧密的同源物一样，也可能介导细胞细胞粘附，从而在肿瘤进展中起关键作用，鉴于许多转移性癌症失去了细胞粘附性。使用创新的蛋白质组学方法，我们还确定了在许多癌症中始终激活的STAT3作为PTPRT底物。这些观察结果强调了确定STAT3是否是PTPRT肿瘤抑制器信号的关键介体以及肿瘤特异性突变如何影响肿瘤生长和细胞细胞粘附的重要性。相关性：拟议的研究将扩大我们对导致结肠癌的新因素的理解。这种关注结肠癌潜在的新靶标的应促进设计新方法治疗癌症患者的方法。