ROLE OF CORTACTIN IN HEAD AND NECK CANCER

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 皮质蛋白是一种皮质肌动蛋白结合蛋白，是多种肿瘤促进致癌激酶的底物。 皮质激素与肌动蛋白相关（阿普）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的肌动蛋白丝聚合来驱动细胞运动。 Corpine在几种人类癌症中过表达，最常见于头颈部鳞状细胞癌（HNSCC），这是染色体11 q13扩增的结果。 HNSCC是困扰口腔和相关组织的最常见的癌症，并且遵循从增生进展到癌的明确定义的范例。我们实验室最近的工作表明，corneumen过表达直接调节HNSCC运动和入侵增强激活Arp 2/3复合物和Src家族激酶介导的酪氨酸磷酸化。 这些研究表明，corneum蛋白过表达在HNSCC侵袭和转移中起直接作用。 然而，在HNSCC中corneumn过表达的精确阶段、corneumn作为HNSCC侵袭的预后标志物的适用性、corneumn相关的分子以及corneumn过表达在HNSCC进展中的影响尚未研究。 该提案将通过三个目标来解决这些问题：目标1将确定HNSCC进展过程中的阶段，在该阶段中，corneum基因座被扩增，并且蛋白质在酪氨酸和丝氨酸残基上过表达/磷酸化。 目的2将通过蛋白质组学方法鉴定在染色体11 q13扩增+/-的HNSCC细胞中与coronin相互作用的蛋白质。目的3建立corneumen转基因小鼠口腔癌模型，以评价corneumen对口腔鳞癌发生发展的影响。

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 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. Cortactin is overexpressed in several human cancers, most frequently in head and neck squamous cell carcinoma (HNSCC) as a result of amplification of chromosome 11q13. HNSCC is the most common cancer that afflicts the oral cavity and associated tissues, and follows a well-defined paradigm of progression from hyperplasia 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 tyrosine phosphorylation mediated by Src-family kinases. These studies suggest that cortactin overexpression plays a direct role in HNSCC invasion and metastasis. 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. This proposal will address these questions through three aims: Aim 1 will determinine the stage(s) during HNSCC progression in which the cortactin locus is amplified, and the protein overexpressed/phosphorylated on tyrosine and serine residues. Aim 2 will identify proteins that interact with cortactin in HNSCC cells +/- chromosome 11q13 amplification by proteomic methods. Aim 3 will develop a transgenic mouse model of cortactin in oral cancer to evaluate how cortactin influences HNSCC development and progression.