Interaction of uPA/R and Integrins in Oral Cancer

描述：（改编自研究者摘要）侵入性行为 口腔癌的发生需要协调的细胞事件， 膜附着和脱离，细胞外基质（ECM）蛋白水解，以及 获得运动性。基质结合整合素的表达改变是 与口腔癌进展相关。整合素可以促进等级 由整合素的物理性质决定的细胞反应 接合，从而转换来自ECM的不同信号。生产 两类不同的ECM降解蛋白酶，纤溶酶原激活剂（PA） 而基质金属蛋白酶（MMP）也是恶性肿瘤的早期事件， 进展丝氨酸蛋白酶表达增强与 尿蛋白酶型PA（uPA或尿激酶）、MMP-9（明胶酶B）与肿瘤 进展被描述得很好。尿型PA（uPA）与其细胞的结合 受体（uPAR）导致增强的细胞周纤溶酶形成，这反过来 直接降解ECIV糖蛋白并激活选定的MMP如MMP-9。 此外，uPAJR还可以通过新的， 不依赖蛋白酶的机制，通过修饰整合素粘附功能， 调节整合素信号通路。我们的数据表明，a3 b1整合素 聚集改变uPA和MMP-9的表达。此外，a3 bl整联蛋白 聚集诱导uPA/R/a3 b 1整合素结合和MAP激酶（MAPK） 激活，导致增强（蛋白酶转录基于这些 结果，这是这项建议的工作假设，一个功能链接 粘附与蛋白质水解之间的关系调节口腔癌的侵袭行为。 具体来说，我们提出了一个多功能的相互作用的uPA/R系统与 癌细胞整联蛋白，使得整联蛋白编辑的粘附调节 细胞，iPA表达，而随后的uPA/uPAR/整合素相互作用， 反过来调节控制蛋白酶表达的下游粘附事件， 增殖、粘附和运动。为了验证这一假设，我们将评估 控制A3 B1整联蛋白接合的特定物理参数 蛋白酶诱导uPAIR调节a3 b1信号传导的能力和 然后分析修饰的蛋白酶表达和增殖。 正常和肿瘤组织的免疫组织化学和生化分析将 用于评价整合素、蛋白酶和MAPK的表达和活性。 诱导性蛋白酶在细胞侵袭中的作用 然后评价表型。拟议研究的长期目标 更详细地了解 粘附和蛋白质水解，以及这种相互作用对调节的影响 转移。

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.