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资助的中心赠款提供的资源的许多研究子项目之一。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。所列机构为中心，不一定是研究者所在机构。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。皮质激素还与肌动蛋白相关的（阿普）2/3蛋白复合物相互作用，该蛋白复合物通过在运动细胞的前缘启动和维持肌动蛋白丝的聚合来驱动细胞运动。Arp 2/3的激活对于板状伪足的形成至关重要，板状伪足是细胞迁移的初始步骤。片状伪足也在肿瘤细胞侵袭中起主要作用，允许癌细胞侵入并扩散到邻近组织中。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区域扩增的结果。HNSCC是困扰口腔和相关组织的最常见的癌症，并且遵循从增生到癌的肿瘤进展的明确定义的范例。我们实验室最近的工作表明，corneumen过表达直接调节HNSCC的运动和入侵，通过增强Arp 2/3复合物的激活和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，在HNSCC中corneumen过表达的精确阶段、corneumen作为HNSCC侵袭的预后标志物的适用性、corneumen相关的分子以及corneumen过表达在HNSCC进展中的影响尚未详细研究。该提案旨在解决这些问题，有三个具体目标：目标1将确定HNSCC进展期间的阶段，即corneum基因座扩增，蛋白质过表达以及何时在酪氨酸和丝氨酸残基上磷酸化。目的2将通过蛋白质组学方法鉴定在染色体11 q13扩增和未扩增的HNSCC细胞中与coronin相互作用的选择蛋白。目的3：建立第一个口腔癌中corn基因的转基因小鼠模型，以评估corn基因过表达对HNSCC发生和发展的影响。还将评价Arp 2/3和酪氨酸磷酸化无效显性失活corneumn点突变体的转基因过表达的影响。完成拟议的目标将提供更好的理解和洞察corneumn在HNSCC中的功能，并可能建立corneumn作为浸润性/转移性HNSCC的预后标志物。