The Role of E-cadherin N-glycans in Oral Cancer

E-钙粘蛋白 N-聚糖在口腔癌中的作用

基本信息

批准号：
7420929
负责人：
MARIA A. KUKURUZINSKA
金额：
$ 28.71万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7420929
关键词：
Actins Adhesions Adhesives Affect Architecture Archives Binding Cancer cell line Cell Proliferation Cell-Cell Adhesion Cells Characteristics Complex Cytoskeleton DNA Sequence Rearrangement Development Diagnosis Down-Regulation E-Cadherin Epidermal Growth Factor Receptor Epithelial Cells Event Extracellular Domain Glycoproteins Goals Growth Human Integral Membrane Protein Intercellular Junctions Invaded Link Localized Malignant Epithelial Cell Malignant Neoplasms Mediating Morphogenesis Mouth Neoplasms Nature Neoplasm Metastasis Numbers Operative Surgical Procedures Oral Patients Phenotype Play Polysaccharides Proliferating Protein Overexpression Research Resected Role SCID Mice Salivary Salivary Glands Signal Pathway Signal Transduction Site Staging Structure Tail Testing Therapeutic Tissues Transmembrane Domain Transplantation Tumor Suppressor Proteins Tumor Tissue Variant adhesion receptor base cancer cell cell motility glycosylation in vivo insight malignant mouth neoplasm migration mouth squamous cell carcinoma mutant novel p27 Cell Cycle Protein p27 Enzyme Inhibitor rho GTP-Binding Proteins salivary cell stable cell line tumor

项目摘要

DESCRIPTION (provided by applicant): Oral cancer constitutes 1 of the most pernicious cancers with only a 5-year predicted survival following diagnosis. Our research proposes to elucidate some of the underlying causes of oral cancer by focusing on the nature of cell-cell contacts in human oral cancer cells. The long-term goal of our studies is to determine the role of N-glycosylation in the formation of E-cadherin-mediated cell-cell contacts in oral cancer cells. E-cadherin, with its documented role as a tumor suppressor, is the principal cell-cell adhesion receptor in oral epithelial cells. Although changes in N-glycan structures have long been known to be corollaries of tumor formation and metastasis, no information is available about how these structures affect E-cadherin adhesive function. E-cadherin ectodomains, which function in the formation of homotypic cell-cell contacts, have several potential N-glycan addition sites, while the cytosolic tail binds catenins that provide the linkage to the actin cytoskeleton. We have shown that during cell proliferation and migration, E-cadherin is extensively N-glycosylated and present in unstable cell-cell contacts. In contrast, in cytodifferentiated cells, E-cadherin is scarcely N-glycosylated and found in stable junctional complexes associated with the actin cytoskeleton. Our initial studies in vivo and ex vivo show that inappropriate increase in E-cadherin N-glycosylation in differentiated salivary cells reverses E-cadherin-mediated cell-cell contacts from stable to weak. Importantly, many cancer cells have highly N-glycosylated E-cadherin that is present in weak cell-cell contacts. Our hypothesis is that the N-glycosylation status of E- cadherin regulates its tumor suppressive function. We propose to test this hypothesis in 4 specific aims: 1) to demonstrate that highly N-glycosylated E-cadherin is a characteristic of oral cancer cell lines; 2) to show that high levels of E-cadherin N-glycosylation drive the formation of unstable E-cadherin-mediated cell-cell contacts; 3) to determine the signaling events through which N-glycosylation status of E-cadherin affects oral cancer cell proliferation and survival; and 4) to show that N-glycosylation status of E-cadherin regulates its tumor suppressive activity in SCID mice in vivo. Our proposed studies will increase the understanding of the basis of E-cadherin tumor suppressive activity in oral cancer and will serve as a basis for the development of novel treatment strategies.

描述（由申请人提供）：口腔癌构成1个最有害的癌症中的1种，诊断后仅5年预测生存。我们的研究建议通过关注人口腔癌细胞的细胞 - 细胞接触性质来阐明口腔癌的某些潜在原因。我们研究的长期目标是确定N-糖基化在口腔癌细胞中E-钙粘蛋白介导的细胞接触形成中的作用。 E-钙粘着蛋白具有记录为肿瘤抑制剂的作用，是口腔上皮细胞中的主要细胞粘附受体。尽管长期以来已知N-聚糖结构的变化是肿瘤形成和转移的推论，但没有有关这些结构如何影响E-钙粘着蛋白粘附功能的信息。 E-钙粘蛋白的外生域在同型细胞 - 细胞接触形成中起作用，具有几个潜在的N-聚糖添加位点，而胞质尾巴则结合了链氨典蛋白，可提供与肌动蛋白细胞骨架的链接。我们已经表明，在细胞增殖和迁移期间，E-钙粘着蛋白是广泛的N-糖基化并存在于不稳定的细胞接触中。相比之下，在细胞区分化的细胞中，E-钙粘着蛋白几乎是N-糖基化的，并且在与肌动蛋白细胞骨架相关的稳定连接络合物中发现。我们在体内和体内的最初研究表明，分化的唾液细胞中E-钙粘着蛋白N-糖基化的不当增加会逆转E-钙粘蛋白介导的细胞 - 细胞接触从稳定到弱。重要的是，许多癌细胞具有高度N-糖基化的E-钙粘着蛋白，存在于弱细胞接触中。我们的假设是，cadherin的N-糖基化状态调节其肿瘤抑制功能。我们建议在4个特定目的中检验这一假设：1）证明高度N-糖基化的E-钙粘蛋白是口服癌细胞系的特征； 2）表明高水平的E-钙粘蛋白N-糖基化驱动不稳定的E-钙粘蛋白介导的细胞 - 细胞接触的形成； 3）确定e-钙粘着蛋白的N-糖基化状态的信号传导事件会影响口腔癌细胞的增殖和存活； 4）表明，E-钙粘蛋白的N-糖基化状态调节其在体内SCID小鼠中的肿瘤抑制活性。我们提出的研究将增加对口腔癌中电子钙粘蛋白抑制活性基础的理解，并将作为发展新治疗策略的基础。