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: 7873024
• 负责人: MARIA A. KUKURUZINSKA
• 金额: $ 28.43万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873024
• 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; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Morphogenesis; Mouth Neoplasms; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Oral; Patients; Phenotype; Play; Polysaccharides; Proliferating; Research; Resected; Role; SCID Mice; Salivary; Salivary Glands; Signal Pathway; Signal Transduction; Site; Staging; Structure; Tail; Testing; 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; overexpression; rho GTP-Binding Proteins; salivary cell; stable cell line; therapeutic development; treatment strategy; 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）：口腔癌是最恶性的癌症之一，诊断后预计生存期仅为 5 年。我们的研究旨在通过关注人类口腔癌细胞中细胞与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间接触形成中的作用。 E-钙粘蛋白具有作为肿瘤抑制因子的作用，是口腔上皮细胞中主要的细胞间粘附受体。尽管人们早已知道 N-聚糖结构的变化是肿瘤形成和转移的必然结果，但尚无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-细胞接触中发挥作用，具有多个潜在的 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。我们已经证明，在细胞增殖和迁移过程中，E-钙粘蛋白被广泛 N-糖基化，并存在于不稳定的细胞-细胞接触中。相反，在细胞分化细胞中，E-钙粘蛋白几乎不被 N-糖基化，并且存在于与肌动蛋白细胞骨架相关的稳定连接复合物中。我们的体内和离体初步研究表明，分化唾液细胞中 E-钙粘蛋白 N-糖基化的不当增加可将 E-钙粘蛋白介导的细胞间接触从稳定逆转为弱。重要的是，许多癌细胞具有高度 N-糖基化的 E-钙粘蛋白，其存在于微弱的细胞-细胞接触中。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。我们建议通过 4 个具体目标来检验这一假设：1）证明高度 N-糖基化的 E-钙粘蛋白是口腔癌细胞系的一个特征； 2) 表明高水平的E-钙粘蛋白N-糖基化驱动了不稳定的E-钙粘蛋白介导的细胞-细胞接触的形成； 3) 确定E-钙粘蛋白的N-糖基化状态影响口腔癌细胞增殖和存活的信号转导事件； 4) 表明E-钙粘蛋白的N-糖基化状态在SCID小鼠体内调节其肿瘤抑制活性。我们提出的研究将增加对口腔癌中 E-钙粘蛋白肿瘤抑制活性基础的了解，并将作为开发新治疗策略的基础。

项目成果

Aberrant amplification of the crosstalk between canonical Wnt signaling and N-glycosylation gene DPAGT1 promotes oral cancer.

• DOI: 10.1016/j.oraloncology.2012.01.010
• 发表时间: 2012-06
• 期刊: ORAL ONCOLOGY
• 影响因子: 4.8
• 作者: Jamal, Basem;Sengupta, Pritam K.;Gao, Zhen-nan;Nita-Lazar, Mihai;Amin, Bakr;Jalisi, Sharuch;Bouchie, Meghan P.;Kukuruzinska, Maria A.
• 通讯作者: Kukuruzinska, Maria A.