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控成分。具体地，纤连蛋白（FN）的可变剪接V区对这些进展是重要的，因为只有含有该区域的FN微蛋白（V+H和V+H-）在体外诱导鳞状细胞癌（SCC）细胞的侵袭和迁移增加。相反，当用V+H-FN蛋白处理时，原代正常角质形成细胞和成纤维细胞经历凋亡。在成纤维细胞中，该机制由硫酸软骨素蛋白聚糖介导，可能由α 4整联蛋白介导，由涉及半胱天冬酶-1和-3的半胱天冬酶级联介导，由p53和c-myc的改变介导，以及由pp 125 FAK的伴随减少介导。这些数据表明，致瘤性使SCC细胞绕过凋亡途径，而是采取了入侵和迁移表型响应V+H-蛋白。据推测，SCC细胞经历增加迁移表型响应V+H-蛋白。假设SCC细胞通过细胞表面蛋白聚糖和整联蛋白受体响应于FN的可变剪接V区而经历增加的侵袭和迁移，所述受体启动不同于初级非转化受体的信号转导途径，其启动不同于初级非表面受体的信号转导途径，参与介导由含V的FN片段诱导的增加的迁移和侵袭。具体而言，确定硫酸软骨素蛋白聚糖和α 4整联蛋白是否参与这种侵袭和迁移机制，因为这些受体调节成纤维细胞中含V FN片段触发的凋亡途径。(2)检查SCC细胞信号应答，其参与介导由含V的FN片段诱导的增加的迁移和侵袭。具体来说，确定p53和c-myc是否像原代细胞中那样被调节。这些研究将有助于解释细胞-基质相互作用的一些基本机制和调节肿瘤细胞生物学的信号机制。此外，由于鳞状细胞癌是最常见的恶性口腔肿瘤，占口腔癌相关死亡的主要部分，这些研究可能提供潜在的有用的治疗干预途径。