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

• 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
• 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

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）：该基金的长期目标是阐明受体蛋白酪氨酸磷酸酶PTPRT突变导致结直肠癌发展的机制。该提案检验了以下假设：PTPRT突变损害关键的肿瘤抑制功能，通过破坏细胞-细胞粘附导致肿瘤生长加速和/或肿瘤进展，并且“信号转导子和转录激活子3”（STAT 3）在PTPRT调节的肿瘤抑制信号传导途径中起关键作用。本提案的第一个目的是研究PTPRT的肿瘤特异性突变是否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STAT 3是否作为PTPRT调节的细胞信号传导途径的关键介质，这在肿瘤发展中是重要的。第三个目标将确定PTPRT胞外结构域中的肿瘤源性突变是否影响细胞-细胞粘附。该建议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%的结直肠癌中突变的6种酪氨酸磷酸酶基因，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是这6个基因中突变频率最高的酪氨酸磷酸酶基因，PTPRT的过表达抑制结直肠癌细胞的生长。该实验室最近的工作表明，PTPRT的细胞外结构域介导嗜同性结合，这表明PTPRT，像它的同源物一样，也可能介导细胞-细胞粘附，因此在肿瘤进展中发挥关键作用，因为许多转移性癌症失去了它们的细胞粘附特性。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STAT 3作为PTPRT底物。这些观察结果强调了确定STAT 3是否是PTPRT肿瘤抑制信号传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-细胞粘附的重要性。相关性：这项拟议的研究将扩大我们对导致结肠癌的新因素的理解。这种对结肠癌潜在新靶点的关注应该有助于设计治疗癌症患者的新方法。