Interaction of uPA/R and Integrins in Oral Cancer

描述：(改编自调查人员的摘要)侵入性行为 口腔癌需要协调的细胞活动，包括基底 膜附着和脱离、细胞外基质(ECM)蛋白分解以及 获得动力。基质结合整合素的表达变化是 与口腔癌进展有关。整合素可以促进层级结构 整合素的物理性质所决定的细胞反应 接合，从而从ECM传递不同的信号。生产 两类截然不同的ECM降解蛋白，纤溶酶原激活物(PA) 而基质金属蛋白酶(MMPs)也在恶性病变的早期事件中起作用 进步。丝氨酸表达增强之间的相关性 尿激酶型纤溶酶原激活剂、明胶酶B与肿瘤 进展被很好地描述了。尿型纤溶酶原激活剂(UPA)与其细胞的结合 受体(UPAR)可促进细胞周围纤溶酶的形成，进而 直接降解ECIV糖蛋白并激活选定的基质金属蛋白酶，如基质金属蛋白酶-9。 此外，uPAJR还可能通过新颖的、 通过改变整合素的黏附功能和 调节整合素信号通路。我们的数据表明a3b1整合素 聚集改变uPA和基质金属蛋白酶-9的表达。此外，a3b1整合素 聚集诱导uPA/R/a3b1整合素结合和MAPK 激活，导致增强(基于这些的蛋白酶转录 结果，这一建议的工作假设是一个功能联系 黏附和蛋白降解之间的关系调节口腔癌的侵袭行为。 具体地说，我们提出了UPA/R系统的多功能交互作用 肿瘤细胞整合素，使整合素编辑的黏附调节 细胞，IPA表达，而随后的uPA/uPAR/整合素相互作用在 进而调节下游的粘连事件，从而控制蛋白酶的表达， 增殖性、粘附性和运动性。为了检验这一假设，我们将评估 控制A3b1整合素结合的特定物理参数 蛋白酶诱导。UPAIR调节a3b1信号和 然后对修饰的蛋白水解酶的表达和增殖情况进行分析。 正常组织和肿瘤组织的免疫组织化学和生化分析 用于评估整合素、蛋白水解酶和MAPK的表达和活性。 诱导蛋白水解酶在细胞侵袭中的作用 然后将对表型进行评估。拟议研究的长期目标是 是为了更详细地理解 黏附和蛋白降解及其在调节中的作用 转移的可能性。

DESCRIPTION: (Adapted from the investigator's abstract) The invasive behavior of oral carcinoma requires coordinated cellular events including basement membrane attachment and detachment, extracellular matrix (ECM) proteolysis, and acquisition of motility. Altered expression of matrix binding integrins is associated with oral carcinoma progression. Integrins can promote an hierarchy of cellular responses dictated by the physical nature of the integrin engagement, thereby transducing distinct signals from the ECM. Production of two distinct classes of ECM-degrading proteinases, plasminogen activators (PA) and matrix metalloproteinases (MMP) is also in early event in malignant progression. The correlation between enhanced expression of the serine proteinase urinary-type PA (uPA or urokinase), MMP-9 (gelatinase B) and tumor progression is well described. Binding of urinary type-PA (uPA) o its cellular receptor (uPAR) leads to enhanced pericellular plasmin formation, which in turn directly degrades ECIV giycoproteins and activates selected MMPs such as MMP-9. Moreover, uPAJR may also regulate invasive behavior via novel, proteinase-independent mechanisms, by modifying integrin adhesive functions and modulating integrin signaling pathways. Our data demonstrate that a3b1 integrin aggregation alters expression of both uPA and MMP-9. Further, a3bl integrin aggregation induces uPA/R/a3b 1 integrin association and MAP kinase (MAPK) activation, resulting in enhance( proteinase transcription Based on these results, it is the working hypothesis of this proposal that a functional link between adhesion and proteolysis regulates oral carcinoma invasive behavior. Specifically we propose a multi-functional interaction of the uPA/R system with carcinoma cell integrins, such that integrin-in edited adhesion modulates cellular, iPA expression, while subsequent uPA/uPAR/integrin interactions in turn regulate downstream adhesive events that control proteinase expression, proliferation, adhesion and motility. To test this hypothesis, we will assess the specific physical parameters of a3b1 integrin engagement that control proteinase induction. The ability of uPAIR to modulate a3b1 signaling and modify proteinase expression and proliferation will then be analyzed. Immunohistochemical and biochemical analysis of normal and tumor tissues will be employed to evaluate integrin, proteinase, and MAPK expression and activity. The functional contribution of induced proteinases to the cellular invasive phenotype will then be evaluated. The long term goal of the proposed research is to provide a more detailed understanding of the functional link between adhesion and proteolysis and the con tribution of this in terplay to regulation of metastasis.