Regulation of Desmosomal Cadherins in Oral Cancer

口腔癌中桥粒钙粘蛋白的调节

• 批准号: 7619471
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619471
• 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）：钙粘蛋白黏附的可逆调节在上皮肿瘤细胞进展中起关键作用。虽然大多数研究都集中在经典钙粘蛋白在癌症中的调节上，但对桥粒钙粘蛋白的重要性关注较少。我们最近发现，表皮生长因子受体（EGFR）抑制可导致口腔鳞状细胞癌（OSCC）细胞中桥粒体钙粘蛋白的积累，增强桥粒组装并增加细胞间粘附强度。我们假设EGFR抑制干扰桥粒钙粘蛋白内化和/或进入降解途径。为了支持这一观点，EGFR抑制剂阻断了细胞质池中desmoglin 2 （Dsg2）的积累，这与基质金属蛋白酶（MMP）依赖的Dsg2外域加工及其细胞质域酪氨酸磷酸化的抑制有关。此外，在高侵袭性SCC68细胞中，mmp抑制阻断了Dsg2的内化，而不是E-cadherin，这提高了桥粒体和经典cadherin的调节可以通过机制解耦的可能性。我们提出了一个模型，EGFR酪氨酸磷酸化和mmp依赖的裂解共同促进桥粒钙粘蛋白复合物的内化和降解，导致OSCC的粘附减弱，侵袭和转移增加。我们将通过以下方式进行测试：1)结合使用共聚焦显微镜、活细胞成像和OSCC的生化分析，评估EGFR/MMP抑制是否通过阻止Dsg2/Dsc2的内化和/或促进Dsg2/Dsc2的内核循环而使桥粒钙粘蛋白脱离降解途径；2)确定Dsg2细胞质结构域和相关犰狳蛋白对桥粒钙粘蛋白细胞表面表达和内化的调节作用；3)确定mmp依赖的Dsg2切割对桥粒钙粘蛋白复合物的内化和降解以及体内肿瘤生长、侵袭和转移的贡献。这些研究将有助于建立头颈癌肿瘤微环境中桥粒钙粘蛋白如何受信号调节的范式。这项工作的结果也将对未来根据钙粘蛋白和MMP状态定制治疗策略具有重要意义。