Regulation of Desmosomal Cadherins in Oral Cancer

口腔癌中桥粒钙粘蛋白的调节

• 批准号: 7805576
• 负责人: Kathleen Janee Green
• 金额: $ 26.03万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7805576
• 关键词: Address; Adhesions; Adhesives; Animal Model; Attention; Binding; Biochemical; Cadherins; Cell Adhesion; Cell surface; Cells; Chimera organism; Complex; Confocal Microscopy; Coupling; Cytoplasmic Tail; Cytoskeleton; Data; Degradation Pathway; Desmosomes; E-Cadherin; Endosomes; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epithelial; Family Dasypodidae; Future; Head and Neck Cancer; In Vitro; Inhibition of Matrix Metalloproteinases Pathway; Intermediate Filaments; Keratin; Life; Light; Malignant Epithelial Cell; Malignant Neoplasms; Matrix Metalloproteinases; Membrane; Modeling; Mouth Neoplasms; Neoplasm Metastasis; Pathway interactions; Play; Process; Proteins; Receptor Inhibition; Recycling; Regulation; Resolution; Role; Route; Signal Transduction; Site; Tail; Testing; Therapeutic; Tissues; Tyrosine; Tyrosine Phosphorylation; Work; armadillo proteins; base; cell motility; cellular imaging; defined contribution; design; desmocollin; desmoglein 2; in vivo; insight; malignant mouth neoplasm; mouth squamous cell carcinoma; mutant; neoplastic cell; prevent; trafficking; tumor; tumor growth

DESCRIPTION (provided by applicant): The reversible modulation of cadherin-based adhesion plays a critical role in epithelial tumor cell progression. Whereas most studies have focused on the regulation of classic cadherins in cancer, less attention has been paid to the importance of desmosomal cadherins. We recently showed that epidermal growth factor receptor (EGFR) inhibition results in the accumulation of desmosomal cadherins in oral squamous cell carcinoma (OSCC) cells, enhancing desmosome assembly and increasing intercellular adhesive strength. We hypothesized that EGFR inhibition interferes with desmosomal cadherin internalization and/or entry into a degradative pathway. Supporting this idea, EGFR inhibitors block accumulation of desmoglein 2 (Dsg2) in a cytoplasmic pool, correlated with inhibition of matrix metalloproteinase (MMP)-dependent processing of the Dsg2 ectodomain and tyrosine phosphorylation of its cytoplasmic domain. Furthermore, MMP-inhibition blocked internalization of Dsg2, but not E-cadherin, in highly invasive SCC68 cells, raising the possibility that regulation of desmosomal and classic cadherins can be uncoupled mechanistically. We propose a model whereby EGFR tyrosine phosphorylation and MMP-dependent cleavage cooperate to promote internalization and degradation of the desmosomal cadherin complex, leading to weakened adhesion, increased invasion and metastasis of OSCC. We will test this by: 1) using a combination of confocal microscopy, live cell imaging and biochemical analysis of OSCC to assess whether EGFR/MMP inhibition diverts desmosomal cadherins from a degradative pathway by preventing internalization and/or promoting endosome recycling of Dsg2/Dsc2, 2) defining the contribution of Dsg2 cytoplasmic domain and associated armadillo proteins to regulation of desmosomal cadherin cell surface expression and internalization, and 3) determining the contribution of MMP-dependent Dsg2 cleavage to internalization and degradation of the desmosomal cadherin complex in vitro and to tumor growth, invasion and metastasis in vivo. These studies will help to establish a paradigm for how desmosomal cadherins are regulated by signals in the tumor microenvironment of head and neck cancers. Results from this work will also have important implications for the future tailoring of therapeutic strategies based on their cadherin and MMP status.

描述（由申请人提供）：基于钙粘着蛋白的粘附的可逆调节在上皮肿瘤细胞进展中起关键作用。 尽管大多数研究都集中在癌症中经典钙粘蛋白的调节上，但对脱乳小蛋白的重要性的关注较少。 我们最近表明，表皮生长因子受体（EGFR）抑制作用导致脱骨钙粘着蛋白在口服鳞状细胞癌（OSCC）细胞中的积累，增强了脱粒体组装并提高细胞间粘合强度。 我们假设EGFR抑制作用会干扰脱骨钙粘着蛋白的内在化和/或进入降解途径。 在支持这一想法的情况下，EGFR抑制剂阻止了desmoglein 2（DSG2）在细胞质库中的积累，与抑制基质金属蛋白酶（MMP）依赖性加工DSG2外生素蛋白蛋白和酪氨酸磷酸化的抑制作用相关。 此外，在高度侵入性的SCC68细胞中，MMP抑制阻止了DSG2的内在化，但不能阻止E-钙粘着蛋白的内在化，从而提高了可能在机械上取消脱骨体和经典钙粘着蛋白的调节的可能性。 我们提出了一个模型，通过该模型，EGFR酪氨酸磷酸化和MMP依赖性裂解合作，以促进脱乳小体钙粘蛋白复合物的内在化和降解，从而导致粘附力减弱，侵袭和OSCC的转移增加。 我们将通过：1）使用共焦显微镜，活细胞成像和OSCC的生化分析的结合来评估EGFR/MMP抑制是否会从降解途径中脱离脱骨钙蛋白，通过预防内在化和/或促进DSG2/DSC2的内在循环效应DSG2/DSC2，2）定义DS的内在化和/或促进内体。 armadillo蛋白可以调节脱褐色钙粘蛋白细胞表面表达和内在化，以及3）确定依赖MMP依赖的DSG2裂解对体外和肿瘤生长和肿瘤生长，侵袭和转移INVIVO的内在化和降解的贡献。 这些研究将有助于建立一个范式，以通过肿瘤微环境的头颈癌的信号来调节脱染色体钙粘着蛋白。 这项工作的结果还将对基于钙粘蛋白和MMP状态的未来对治疗策略的量身定制有重要意义。