Interaction of uPA/R and Integrins in Oral Cancer

描述（由申请人提供）：口腔鳞状细胞癌（OSCC）是口腔最常见的恶性肿瘤。 在过去的20年中，5年生存率一直保持在50%的低水平，突出了我们对控制口腔鳞癌发生、进展和转移的分子事件的有限理解。 由于口腔鳞状细胞癌的高死亡率归因于转移，更详细的分析，加强口腔鳞状细胞癌传播的分子事件是一个必要的先决条件，新的早期检测和治疗策略的发展。 对与口腔鳞癌转移相关的表观遗传学变化的分析表明，E-cadherin的丢失沿着尿型纤溶酶原激活物（uPA）和？3整合素作为预测不良疾病结局的关键候选生物标志物。 蛋白酶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修饰，增强侵袭和转移。 此外，在前一个资助期内获得的结果已经确定了基质诱导的uPA/R之间的物理相互作用和？三个？1整联蛋白，启动Src/MEK/ERK依赖性信号通路，最终激活uPA启动子。 与整合素信号传导相反，通过形成从头连接激活E-钙粘蛋白抑制蛋白酶活性和侵袭。 之间的串扰？三个？1整联蛋白和E-钙粘蛋白是明显的，因为整联蛋白聚集下调表面E-钙粘蛋白，从而使细胞-细胞连接接触不稳定。 这些数据支持这一假设，即粘附和蛋白水解之间的功能联系调节口腔鳞状细胞癌的侵袭行为。 拟议的实验将阐明机制，uPAR，作为一个横向？三个？1整合素配体，可以调节？三个？1信号转导，从而调节OSCC转移行为。 目标1中提出的实验将集中在基质调节uPAR/？三个？1膜动力学阐明机制，脂筏分区uPAR/？三个？1可以调节信号转导和改变基因表达。 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和？连接蛋白介导的转录对连接溶解的响应。 这些机制数据将整合在目标3中，以评估OSCC进展中的表观遗传因素，使用更准确地反映体内微环境的体外和体内模型系统。 总之，这些实验将提供新的数据机制，使横向相互作用的uPAR？三个？1整合素有助于口腔鳞癌肿瘤的传播，并可能提供长期的研究，针对这种相互作用作为一种新的治疗策略的基本原理。

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.