ROLE OF CORTACTIN IN HEAD AND NECK CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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与肌动蛋白相关(Arp)2/3蛋白复合体相互作用，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。由于染色体11q13的扩增，Cortactin在几种人类癌症中过表达，最常见的是在头颈部鳞状细胞癌(HNSCC)中。HNSCC是困扰口腔及相关组织的最常见的癌症，遵循明确的从增生到癌的进展模式。我们实验室最近的工作表明，Cortactin的过表达通过增强Arp2/3复合体的激活和通过Src家族激酶介导的酪氨酸磷酸化来直接调节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。然而，在HNSCC中皮层肌动蛋白过度表达的确切阶段、是否适合作为HNSCC侵袭的预后标志物、与皮质肌动蛋白相关的分子以及在HNSCC进展中的影响还没有被研究。这项建议将通过三个目标来解决这些问题：目标1将确定HNSCC进展过程中皮质蛋白基因座扩增的阶段(S)，以及蛋白质在酪氨酸和丝氨酸残基上的过度表达/磷酸化。目的2通过蛋白质组学方法鉴定HNSCC细胞中与皮质素相互作用的蛋白质/-染色体11q13扩增。目的3将建立口腔癌皮质酮转基因小鼠模型，以评价皮质酮对HNSCC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.