Cortactin Binding Partners in HNSCC Phenotypes

HNSCC 表型中的 Cortactin 结合伙伴

基本信息

批准号：
8060206
负责人：
Christi Lynn French
金额：
$ 3.58万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-03 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8060206
关键词：
11q13 Actin-Binding Protein Actins Address Affect Aggressive behavior Anchorage-Independent Growth Binding Binding Proteins Breast CD2-associated protein Cell Line Cytoskeleton DNA DNA Sequence Rearrangement Data Dynamin EMS1 gene F-Actin Genomics Goals Golgi Apparatus Grant Head and Neck Squamous Cell Carcinoma Human In Vitro Laboratories Link Malignant Epithelial Cell Malignant Neoplasms Matrix Metalloproteinases Mediating Membrane Protein Traffic Messenger RNA Molecular Morphology Myosin Light Chain Kinase Peptide Hydrolases Phenotype Prostate Protein Binding Proteins Regulation Role SH3 Domains Serum Structure Survival Rate Testing Tissues Wasps Wiskott-Aldrich Syndrome Work Xenograft Model abstracting autocrine base cancer cell cancer type human EMS1 protein in vivo knock-down migration mutant neoplastic cell new therapeutic target numb protein outcome forecast overexpression protein protein interaction public health relevance relating to nervous system research study small hairpin RNA src-Family Kinases therapeutic target tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world, and there has been only a limited increase in survival rate over the last 30 years unlike the significant survival improvements in better-studied cancer types such as breast and prostate. Although molecular alterations are overall poorly characterized in HNSCC, the actin-binding protein cortactin has been shown to be overexpressed in 30-40% of HNSCC, due to the presence of its gene (CTTN) in the 11q13 amplicon. Importantly, numerous studies have shown that cortactin overexpression at the protein, mRNA and genomic DNA levels is highly correlated with poor prognosis. Cortactin was originally identified as a src kinase substrate, and has been shown to be important in actin cytoskeleton rearrangement, migration, and invasion. Our laboratory has shown cortactin to be important for various cancer-associated phenotypes in HNSCC, including tumor growth and invasion, serum- and anchorage-independent growth, migration and invadopodia formation. Our recent data suggest that underlying mechanisms for these phenotypes include alterations in membrane trafficking, with consequent regulation in secretion of proteinases and other autocrine secreted factors. Cortactin binds to a number of proteins necessary for cancer progression, including Src kinase and filamentous actin (F-actin). However, the molecular mechanisms and cortactin-binding proteins that are important for these functions of cortactin have yet to be elucidated. To determine the molecular interactions of cortactin that are important in promoting tumor aggression, I propose two specific aims: 1, to determine which cortactin binding interactions are critical for cortactin-dependent HNSCC cell phenotypes in vitro and in vivo; and 2, to test the role of cortactin binding partners in cortactin-sensitive cellular phenotypes. By investigating these aims, I hope to identify new potential therapeutic targets for treatment of HNSCC. PUBLIC HEALTH RELEVANCE: The actin binding gene cortactin is overexpressed in 30-40% of head and neck squamous cell carcinoma, and generally correlates with poor prognosis and more aggressive cases. However, the molecular mechanisms by which cortactin promotes aggressiveness are poorly understood. This proposal seeks to elucidate which cortactin binding partners and domains are critical for tumor cell phenotypes.

描述（由申请人提供）：摘要：头颈鳞状细胞癌 (HNSCC) 是世界上第六大常见癌症类型，与显着的生存改善不同，过去 30 年生存率仅增加有限。在乳腺癌和前列腺癌等经过更好研究的癌症类型中。尽管 HNSCC 中的分子改变总体上表征不佳，但由于 11q13 扩增子中存在其基因 (CTTN)，肌动蛋白结合蛋白 cortactin 已被证明在 30-40% 的 HNSCC 中过度表达。重要的是，大量研究表明 cortactin 在蛋白质、mRNA 和基因组 DNA 水平上的过度表达与不良预后高度相关。 Cortactin 最初被鉴定为 src 激酶底物，并已被证明在肌动蛋白细胞骨架重排、迁移和侵袭中发挥重要作用。我们的实验室已证明皮质素对于 HNSCC 中的各种癌症相关表型非常重要，包括肿瘤生长和侵袭、血清和贴壁依赖性生长、迁移和侵袭伪足形成。我们最近的数据表明，这些表型的潜在机制包括膜运输的改变，以及随后对蛋白酶和其他自分泌因子的分泌的调节。 Cortactin 与癌症进展所需的许多蛋白质结合，包括 Src 激酶和丝状肌动蛋白 (F-肌动蛋白)。然而，对于皮质素的这些功能很重要的分子机制和皮质素结合蛋白尚未阐明。为了确定在促进肿瘤侵袭中重要的 Cortactin 分子相互作用，我提出了两个具体目标：1，确定哪些 Cortactin 结合相互作用对于体外和体内 Cortactin 依赖性 HNSCC 细胞表型至关重要； 2、测试cortactin结合伴侣在cortactin敏感细胞表型中的作用。通过研究这些目标，我希望找到治疗 HNSCC 的新的潜在治疗靶点。公共健康相关性：肌动蛋白结合基因 cortactin 在 30-40% 的头颈鳞状细胞癌中过度表达，通常与预后不良和更具侵袭性的病例相关。然而，人们对皮质素促进攻击性的分子机制知之甚少。该提案旨在阐明哪些皮质蛋白结合伴侣和结构域对于肿瘤细胞表型至关重要。