ROLE OF CORTACTIN IN HEAD AND NECK CANCER

Cortactin 在头颈癌中的作用

• 批准号: 7381277
• 负责人: Scott A Weed
• 金额: $ 25.56万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381277
• 关键词: actin binding protein; head; head /neck neoplasm; role

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cortactin is a cortical actin-binding protein and substrate for various tumor-promoting oncogenic kinases. Cortactin also interacts with the actin-related (Arp) 2/3 protein complex, which drives cell motility by initiating and maintaining polymerization of actin filaments at the leading edge of motile cells. Arp2/3 activation is critical for the formation of lamellipodia, the initial step involved in cell migration. Lamellipodia also play a major role in tumor cell invasion, allowing cancer cells to invade and spread into adjacent tissues. Cortactin is overexpressed in several human cancers, most frequently in head and neck squamous cell carcinoma (HNSCC) as a result of amplification of the chromosome 11q13 region. HNSCC is the most common cancer that afflicts the oral cavity and associated tissues, and follows a well-defined paradigm of tumor progression from hyperplasia through to carcinoma. Recent work from our laboratory has demonstrated that cortactin overexpression directly modulates HNSCC motility and invasion by enhanced activation of Arp2/3 complex and by its tyrosine phosphorylation mediated by Src-family kinases. These studies suggest that cortactin overexpression plays a direct role in HNSCC invasion and metastasis, and likely exerts a negative influence on patient outcome. However, the precise stage in HNSCC that cortactin is overexpressed, the suitability of cortactin as a prognostic marker for HNSCC invasion, the molecules cortactin associates with and the influence of cortactin overexpression in HNSCC progression have not been investigated in detail. This proposal seeks to address these questions throught three specific aims: Aim 1 will determining the stage(s) during HNSCC progression is the cortactin locus is amplified, the protein overexpressed and when is it phosphorylated on tyrosine and serine residues. Aim 2 will identify select proteins that interact with cortactin in HNSCC cells with and without chromosome 11q13 amplification by proteomic methods. Aim 3 will develop the first transgenic mouse model of cortactin in oral cancer to evaluate how cortactin overexpression influences HNSCC development and progression. The impact of transgenic overexpression of Arp2/3 and tyrosine phosphorylation-null dominant negative cortactin point mutants will be also be evaluated. Completion of the proposed Aims will provide better understanding and insight into the function of cortactin in HNSCC, and will potentially establish cortactin as a prognostic marker for invasive/metastatic HNSCC.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。 Cortactin 是一种皮质肌动蛋白结合蛋白，也是各种促肿瘤致癌激酶的底物。 Cortactin 还与肌动蛋白相关 (Arp) 2/3 蛋白复合物相互作用，后者通过启动和维持运动细胞前缘肌动蛋白丝的聚合来驱动细胞运动。 Arp2/3 的激活对于片状伪足的形成至关重要，片状伪足是细胞迁移的第一步。板状伪足在肿瘤细胞侵袭中也发挥着重要作用，使癌细胞能够侵入并扩散到邻近组织。 Cortactin 在多种人类癌症中过度表达，最常见的是由于染色体 11q13 区域扩增而导致的头颈鳞状细胞癌 (HNSCC)。 HNSCC 是影响口腔和相关组织的最常见癌症，并且遵循从增生到癌的肿瘤进展的明确范例。我们实验室最近的工作表明，cortactin 过度表达通过增强 Arp2/3 复合物的激活及其由 Src 家族激酶介导的酪氨酸磷酸化，直接调节 HNSCC 的运动和侵袭。这些研究表明，cortactin 过度表达在 HNSCC 侵袭和转移中发挥直接作用，并可能对患者预后产生负面影响。然而，cortactin 在 HNSCC 中过度表达的精确阶段、cortactin 作为 HNSCC 侵袭预后标志物的适用性、cortactin 相关分子以及 cortactin 过度表达对 HNSCC 进展的影响尚未得到详细研究。该提案旨在通过三个具体目标解决这些问题：目标 1 将确定 HNSCC 进展过程中的阶段：皮质蛋白基因座扩增、蛋白质过度表达以及酪氨酸和丝氨酸残基何时磷酸化。目标 2 将通过蛋白质组学方法鉴定在有或没有染色体 11q13 扩增的 HNSCC 细胞中与 Cortactin 相互作用的精选蛋白质。目标 3 将开发第一个口腔癌 Cortactin 转基因小鼠模型，以评估 Cortactin 过度表达如何影响 HNSCC 的发生和进展。还将评估 Arp2/3 转基因过表达和酪氨酸磷酸化无效的显性失活 cortactin 点突变体的影响。完成拟议的目标将有助于更好地理解和深入了解 Cortactin 在 HNSCC 中的功能，并有可能将 Cortactin 确立为侵袭性/转移性 HNSCC 的预后标志物。