Cortactin Binding Partners in HNSCC Phenotypes

HNSCC 表型中的 Cortactin 结合伙伴

基本信息

批准号：
8339870
负责人：
Christi Lynn French
金额：
$ 3.66万
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/8339870
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 Tumor Cell Invasion 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 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：头部和颈部鳞状细胞癌（HNSCC）是世界上第六种最常见的癌症类型，在过去30年中，存活率在过去30年中只有有限的增长，这与精心研究的癌症类型（如乳房和前列腺）的显着生存改善不同。尽管在HNSCC中的分子改变总体上的特征总体上很差，但由于其基因（CTTN）在11q13扩增子中存在基因（CTTN），因此已证明30-40％的HNSCC中，肌动蛋白结合蛋白皮质素在HNSCC的30-40％中过表达。重要的是，许多研究表明，在蛋白质，mRNA和基因组DNA水平上的皮质素过表达与预后不良高度相关。 Cortactin最初被鉴定为SRC激酶底物，并且已证明在肌动蛋白细胞骨架重排，迁移和侵袭中很重要。我们的实验室表明，皮质素对HNSCC中各种癌症相关的表型至关重要，包括肿瘤生长和浸润，血清和锚定的非依赖性生长，迁移和Invadopodia的形成。我们最近的数据表明，这些表型的基本机制包括膜运输的改变，因此对蛋白酶和其他自分泌分泌因子的分泌进行了调节。皮质素与包括SRC激酶和丝状肌动蛋白（F-肌动蛋白）在内的癌症进展所必需的许多蛋白质结合。然而，对于这些功能，尚未阐明分子机制和皮质素结合蛋白。为了确定在促进肿瘤攻击中重要的皮质素的分子相互作用，我提出了两个具体的目的：1，以确定哪些皮质素结合相互作用对于在体外和体内对于依赖皮尔塔素依赖性的HNSCC细胞表型至关重要。 2，测试皮质素结合伴侣在皮质素敏感细胞表型中的作用。通过研究这些目标，我希望确定HNSCC治疗的新潜在治疗靶标。公共卫生相关性：肌动蛋白结合基因cortactin在30-40％的头颈部鳞状细胞癌中过表达，并且通常与预后不良和更具侵略性的病例相关。然而，促进cortactin促进攻击性的分子机制知之甚少。该建议旨在阐明哪些皮质素结合伴侣和域对于肿瘤细胞表型至关重要。