PILOT--INVASION REGULATED BY FIBRONECTIN AND RECEPTORS

飞行员——由纤连蛋白和受体调节的入侵

• 批准号: 6893685
• 负责人: Yvonne L Kapila
• 金额: $ 2.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893685
• 关键词: cell migration; chondroitin sulfates; extracellular matrix; fibronectins; integrins; mouth neoplasms; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic transformation; p53 gene /protein; protein protein interaction; protein structure function; proteoglycan; protooncogene; squamous cell carcinoma; tissue /cell culture

The extracellular matrix is an important regulatory component of tumor cell invasion and migration. Specifically, the alternatively spliced V region of fibronectin (FN) is important to these progresses since only FN miniproteins (V+H and V+H-) containing this region induce increased invasion and migration of squamous cell carcinoma (SCC) cells in vitro. In contrast, primary normal keratinocytes and fibroblasts undergo apoptosis when treated with the V+H-FN protein. In fibroblasts, this mechanism is mediated by chondroitin sulfate proteoglycans, possibly by the alpha 4 integrin, by a caspase cascade involving caspase-1 and -3, by alterations in p53 and c-myc, and by a concomitant decrease in pp125 FAK. These data suggest that tumorigenicity has enabled SCC cells to bypass the apoptotic pathway and instead take on an invasive and migratory phenotype in response to the V+H- protein. It is hypothesized that SCC cells undergo increased migratory phenotype in response to the V+H- protein. It is hypothesized that SCC cells undergo increased invasion and migration in response to the alternatively spliced V region of FN via cell surface proteoglycan and integrin receptors, which initiate a signal transduction pathway that differs from that in primary non- transformed receptors, which initiate a signal transduction pathway that differs from that in primary non-surface receptor(s) involved in mediating increased migration and invasion induced by the V-containing FN fragments. Specifically, determine whether condroitin sulfate proteoglycans and the alpha4 integrin are involved in this mechanism of invasion and migration, since these receptors regulate the apoptotic pathway triggered by the V-containing FN fragment in fibroblasts. (2) Examine the SCC cell signaling response involved in mediating increased migration and invasion induced by the V-containing FN fragments. Specifically, determine whether p53 and c-myc are modulated as in the primary cells. These studies will help explain some of the basic mechanisms underlying the cell-matrix interactions and signaling mechanism that regulate tumor cell biology. In addition, since squamous cell carcinoma is the most common type of malignant oral neoplasm, accounting for a major portion of deaths related to oral cancer, these studies may provide potentially useful avenues for therapeutic intervention.

细胞外基质是肿瘤细胞侵袭和迁移的重要调节成分。具体而言，纤连蛋白（FN）的剪接V区域（FN）对这些进展很重要，因为仅含有该区域的FN微蛋白（V+H和V+H-）会导致鳞状细胞癌（SCC）细胞的侵袭和迁移增加。相反，用V+H-FN蛋白治疗的原发性正常角质形成细胞和成纤维细胞会发生凋亡。在成纤维细胞中，该机制是由硫酸软骨蛋白蛋白聚糖介导的，可能是Alpha 4整合素，涉及caspase-1和-3的caspase Cascade，通过p53和c-Myc的变化，以及在PP125 fak中的同步降低。这些数据表明，肿瘤性使SCC细胞能够绕过凋亡途径，而是对V+H蛋白的侵入性和迁移表型进行了侵入性和迁移表型。假设SCC细胞对V+H-蛋白的响应进行了增加的迁移表型。据推测，SCC细胞通过细胞表面蛋白聚糖和整联蛋白受体的替代剪接的V区域而受到侵袭和迁移的增加，从而引发了信号转导途径，这些信号传递途径与原发性非转化受体不同，该途径在非属性受体中涉及的cription子受受体的迁移（s）的迁移（s）涉及的偏差（s）涉及非菌体（S）的迁移（s）。 FN碎片。具体而言，确定硫酸盐蛋白聚糖和α4整合素是否参与了这种侵袭和迁移机制，因为这些受体调节了成纤维细胞中含有VN的FN片段触发的凋亡途径。 （2）检查涉及介导含Vn的FN片段引起的迁移和侵袭的SCC细胞信号反应。具体而言，确定p53和c-myc是否像原代细胞中一样调制。这些研究将有助于解释细胞 - 基质相互作用和调节肿瘤细胞生物学的信号传导机制的基本机制。此外，由于鳞状细胞癌是最常见的恶性口腔肿瘤类型，这是与口腔癌有关的主要死亡的主要部分，因此这些研究可能为治疗干预提供了潜在的有用途径。