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）：该资助的长期目标是阐明受体蛋白酪氨酸磷酸酶 PTPRT 的突变导致结直肠癌发生的机制。该提案测试了以下假设：PTPRT 突变会损害关键的肿瘤抑制功能，通过破坏细胞间粘附而加速肿瘤生长和/或肿瘤进展，并且“信号转导器和转录激活剂 3”(STAT3) 在 PTPRT 调节中发挥关键作用肿瘤抑制信号通路。该提案的第一个目标是研究 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功能。第二个目标将确定 STAT3 是否充当 PTPRT 调节的细胞信号传导途径的关键介质，这在肿瘤发展中很重要。第三个目标将确定 PTPRT 胞外域中肿瘤衍生的突变是否影响细胞间粘附。该提案建立在我们成功利用癌症基因组方法的基础上，该方法系统地探索了蛋白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 26% 的结直肠癌中有 6 个酪氨酸磷酸酶基因发生突变，这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发挥着关键作用。 PTPRT是六个基因中突变最频繁的酪氨酸磷酸酶基因，PTPRT的过度表达会抑制结直肠癌细胞的生长。该实验室最近的工作表明，PTPRT 的胞外结构域介导同源性结合，这表明 PTPRT 与其密切同源物一样，也可能介导细胞间粘附，从而在肿瘤进展中发挥关键作用，因为许多转移性肿瘤癌症失去细胞粘附特性。使用创新的蛋白质组学方法，我们还鉴定了在许多癌症中持续激活的 STAT3 作为 PTPRT 底物。这些观察强调了确定 STAT3 是否是 PTPRT 肿瘤抑制信号转导的关键介质以及肿瘤特异性突变如何影响肿瘤生长和细胞间粘附的重要性。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。对结肠癌新靶标的关注应有助于设计治疗癌症患者的新方法。