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

• 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
• 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

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）：口腔癌是最致命的癌症之一，诊断后预测生存期仅为5年。我们的研究旨在通过关注人类口腔癌细胞中细胞-细胞接触的性质来阐明口腔癌的一些根本原因。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-细胞接触形成中的作用。E-钙粘蛋白是口腔上皮细胞中主要的细胞间粘附受体，具有肿瘤抑制作用。虽然N-聚糖结构的变化早已被认为是肿瘤形成和转移的必然结果，但没有关于这些结构如何影响E-钙粘蛋白粘附功能的信息。E-钙粘蛋白胞外域在形成同型细胞与细胞接触中发挥作用，具有几个潜在的N-聚糖添加位点，而胞质尾部结合连环蛋白，提供与肌动蛋白细胞骨架的连接。我们已经表明，在细胞增殖和迁移，E-钙粘蛋白是广泛的N-糖基化，并存在于不稳定的细胞-细胞接触。相反，在细胞分化的细胞中，E-钙粘蛋白几乎没有N-糖基化，并在与肌动蛋白细胞骨架相关的稳定连接复合物中发现。我们的初步研究在体内和离体显示，不适当的增加在分化的唾液细胞的E-钙粘蛋白N-糖基化逆转E-钙粘蛋白介导的细胞-细胞接触从稳定到弱。重要的是，许多癌细胞具有存在于弱细胞-细胞接触中的高度N-糖基化的E-钙粘蛋白。我们的假设是E-钙粘蛋白的N-糖基化状态调节其肿瘤抑制功能。我们拟从4个方面验证这一假说：1）证明高度N-糖基化的E-cadherin是口腔癌细胞系的特征; 2）证明高水平的E-cadherin N-糖基化驱动不稳定的E-cadherin介导的细胞-细胞接触的形成; 3）确定E-cadherin N-糖基化状态影响口腔癌细胞增殖和存活的信号事件;和4）显示E-钙粘蛋白的N-糖基化状态调节其在SCID小鼠体内的肿瘤抑制活性。我们提出的研究将增加对E-钙粘蛋白在口腔癌中肿瘤抑制活性的基础的理解，并将作为开发新的治疗策略的基础。