ROLE OF CORTACTIN IN HEAD AND NECK CANCER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。Cortactin是一种皮质肌动蛋白结合蛋白，是多种促癌蛋白的底物。Cortactin还与肌动蛋白相关(Arp)2/3蛋白复合体相互作用，该复合体通过启动和维持运动细胞前沿的肌动蛋白细丝聚合来驱动细胞运动。Arp2/3的激活对片状脂膜的形成至关重要，片状脂膜是细胞迁移的初始步骤。片状脂体也在肿瘤细胞侵袭中发挥重要作用，允许癌细胞侵袭并扩散到邻近组织。Cortactin在几种人类癌症中过表达，最常见的是头颈部鳞状细胞癌(HNSCC)，这是由于染色体11q13区域扩增的结果。HNSCC是困扰口腔及相关组织的最常见的癌症，遵循从增生到癌症的明确的肿瘤进展范例。我们实验室最近的工作表明，Cortactin的过表达通过增强Arp2/3复合体的激活及其由Src家族激酶介导的酪氨酸磷酸化来直接调控HNSCC的运动和侵袭。这些研究表明，Cortactin的过度表达在HNSCC的侵袭和转移中起直接作用，并可能对患者的预后产生负面影响。然而，皮质肌动蛋白在HNSCC中高表达的确切阶段、作为HNSCC侵袭预后标志物的适宜性、与其相关的分子以及在HNSCC进展中的影响还没有详细的研究。这项建议试图通过三个具体目标来解决这些问题：目标1将决定HNSCC进展的阶段(S)是皮质肌动蛋白基因座被放大，蛋白质过度表达，以及它在酪氨酸和丝氨酸残基上何时被磷酸化。目的2通过蛋白质组学方法在HNSCC细胞中筛选与皮质蛋白相互作用的蛋白质，并对扩增和不扩增11q13染色体的细胞进行鉴定。目的3将建立第一个口腔癌皮质酮转基因小鼠模型，以评估皮质酮过表达如何影响HNSCC的发生和发展。还将评估转基因过表达Arp2/3和酪氨酸磷酸化缺失的显性负皮质素点突变的影响。这些目标的完成将有助于更好地理解和洞察皮质蛋白在HNSCC中的作用，并有可能将其作为预测侵袭性/转移性HNSCC的标志物。

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.