Regulation of Desmosomal Cadherins in Oral Cancer

口腔癌中桥粒钙粘蛋白的调节

• 批准号: 7129708
• 负责人: Kathleen Janee Green
• 金额: $ 26.76万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7129708
• 关键词: cadherins; mouth neoplasms

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(申请人提供)：基于钙粘附素的黏附的可逆调节在上皮性肿瘤细胞的进展中起着关键作用。虽然大多数研究都集中在经典钙粘附素在癌症中的调节，但对桥粒钙粘附素的重要性关注较少。我们最近发现，抑制表皮生长因子受体(EGFR)会导致口腔鳞状细胞癌(OSCC)细胞中桥粒钙粘附素的积聚，促进桥粒组装，增加细胞间的黏附强度。我们假设，EGFR抑制干扰了桥粒钙粘附素的内化和/或进入降解途径。支持这一观点的是，EGFR抑制剂阻止桥粒芯糖蛋白2(Dsg2)在细胞质池中的积累，这与抑制依赖于基质金属蛋白酶(MMP)的Dsg2胞外结构域的加工及其胞浆结构域的酪氨酸磷酸化有关。此外，在高侵袭性的SCC68细胞中，基质金属蛋白酶的抑制抑制了Dsg2的内化，但不能阻止E-钙粘蛋白的内化，这增加了桥粒和经典钙粘附素的调节可以机械地解偶联的可能性。我们提出了一个模型，EGFR酪氨酸磷酸化和基质金属蛋白酶依赖的切割协同作用，促进桥粒钙粘附素复合体的内化和降解，导致口腔鳞癌黏附减弱，侵袭和转移增加。我们将通过以下方法来测试这一点：1)结合共聚焦显微镜、活细胞成像和口腔鳞状细胞癌的生化分析来评估EGFR/MMP抑制是否通过阻止Dsg2/Dsc2的内化和/或促进内小体循环来转移桥粒钙粘蛋白的降解途径；2)确定Dsg2细胞质结构域和相关的Aradillo蛋白对桥粒钙粘蛋白细胞表面表达和内化的调节作用；以及3)确定依赖于基质金属蛋白酶的Dsg2裂解对桥粒钙粘附素复合体的体外内化和降解以及对体内肿瘤的生长、侵袭和转移的贡献。这些研究将有助于建立桥粒钙粘附素如何在头颈癌的肿瘤微环境中受到信号调控的范例。这项工作的结果也将对基于钙粘附素和基质金属蛋白酶状态的未来治疗策略的定制具有重要意义。