Interaction of uPA/R and Integrins in Oral Cancer

描述(申请人提供)：口腔鳞状细胞癌(OSCC)是最常见的口腔恶性肿瘤。在过去的20年里，5年生存率一直保持在50%的低水平，这突显了我们对控制口腔鳞状细胞癌发生、发展和转移的分子事件的有限了解。由于口腔鳞癌的高死亡率归因于转移，对促进口腔鳞癌扩散的分子事件进行更详细的分析是开发新的早期发现和治疗策略的必要前提。对与口腔鳞癌转移相关的表观遗传学改变的分析发现，E-钙粘附素的缺失以及尿型纤溶酶原激活物(UPA)和β3整合素的表达增强是预测不良疾病预后的关键候选生物标志物。蛋白水解酶uPA与糖基磷脂酰肌醇(GPI)连接的受体uPAR结合，从而启动酶原激活级联反应，导致基底膜蛋白的蛋白水解性修饰，增强侵袭和转移。此外，在之前的资助期间获得的结果已经证实了uPA/R和β3？1整合素之间存在基质诱导的物理相互作用，该相互作用启动了一个依赖于Src/MEK/ERK的信号通路，最终导致uPA启动子的激活。与整合素信号不同，E-钙粘附素通过形成新生连接而激活，从而抑制了蛋白酶的活性和侵袭。？3？1整合素和E-钙粘附素之间的串扰很明显，因为整合素聚集下调表面E-钙粘附素，从而破坏细胞-细胞连接接触的稳定。这些数据支持黏附和蛋白降解之间的功能联系调节口腔鳞癌侵袭行为的假设。建议的实验将阐明uPAR作为一种侧向整合素配体，可以调节？31？1信号从而调节口腔鳞癌转移行为的机制。目标1中提出的实验将侧重于uPAR/3 1膜动力学的基质调节，以阐明uPAR/3 1脂筏分配调节信号转导和改变基因表达的机制。目的2将评估uPAR调节整合素调节的E-钙粘蛋白连接完整性变化和连接蛋白介导的转录激活对连接溶解的反应的机制。这些机制数据将被整合到AIM 3中，以使用更准确地反映体内微环境的体外和体内模型系统来评估口腔鳞癌进展中的表观遗传因素。总之，这些实验将为uPAR与整合素侧向相互作用促进口腔鳞癌肿瘤扩散的机制提供新的数据，并可能为将这种相互作用作为一种新的治疗策略的长期研究提供理论基础。

DESCRIPTION (provided by applicant): Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. The 5-year survival rate has remained at a low 50% for the past 20 years, highlighting our limited understanding of the molecular events that govern OSCC initiation, progression and metastasis. As the high mortality from OSCC is attributed to metastasis, a more detailed analysis of the molecular events that potentiate OSCC dissemination are a necessary prerequisite to the development of novel early detection and treatment strategies. Analysis of epigenetic changes associated with OSCC metastasis has identified loss of E-cadherin along with enhanced expression of urinary type plasminogen activator (uPA) and ?3 integrin as key candidate biomarkers for prediction of poor disease outcome. The proteinase uPA binds to a glycosylphosphatidyl inositol (GPI)-linked receptor, uPAR, whereupon it initiates zymogen activation cascades leading to proteolytic modification of basement membrane proteins, potentiating invasion and metastasis. Furthermore, results obtained during the previous funding period have identified a matrix- induced physical interaction between uPA/R and ?3?1 integrin that initiates a Src/MEK/ERK-dependent signaling pathway culminating in activation of the uPA promoter. In contrast to integrin signaling, activation of E-cadherin through formation of de novo junctions represses proteinase activity and invasion. Cross-talk between ?3?1 integrin and E-cadherin is evident, as integrin clustering downregulates surface E-cadherin, thereby destabilizing cell-cell junctional contacts. These data support the hypothesis that a functional link between adhesion and proteolysis regulates OSCC invasive behavior. Proposed experiments will elucidate mechanisms by which uPAR, as a lateral ?3?1 integrin ligand, can modulate ?3?1 signaling and thereby regulate OSCC metastatic behavior. Experiments proposed in Aim 1 will focus on matrix regulation of uPAR/?3?1 membrane dynamics to elucidate mechanisms whereby lipid raft partitioning of uPAR/?3?1 can regulate signal transduction and alter gene expression. Aim 2 will evaluate the mechanisms by which uPAR modulates integrin-regulated changes in E-cadherin junctional integrity and activation of ?-catenin-mediated transcription in response to junction dissolution. These mechanistic data will be integrated in Aim 3 to assess epigenetic factors in OSCC progression using in vitro and in vivo model systems that more accurately reflect the in vivo microenvironment. Together these experiments will provide novel data on mechanisms whereby lateral interactions of uPAR with ?3?1 integrin contribute to OSCC tumor dissemination and may provide the rationale for long-term studies that target this interaction as a novel therapeutic strategy.