Ets-1 Expression in Squamous Cells of the Oral Cavity

口腔鳞状细胞中 Ets-1 的表达

基本信息

批准号：
7257725
负责人：
LEE ANN Garrett-Sinha
金额：
$ 3.96万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7257725
关键词：
Animals Apoptosis Behavior Biochemical Biological Models Cell Cycle Progression Cells Coupled Defect Development Diagnostic Neoplasm Staging Down-Regulation Epithelial Epithelium Exhibits Extracellular Matrix Degradation Fibroblast Growth Factor Gene Expression Gene Targeting Genes Genetic Growth Factor Receptors Human Invasive Lead Liver Malignant Conversion Malignant Squamous Cell Neoplasm Metalloproteases Modeling Molecular Mouth Neoplasms Mus Neoplasm Metastasis Neoplasms Oncogenes Oral Oral cavity Ovary Pathway interactions Patients Phenotype Process Property Research Design Research Personnel Role Skin Neoplasms Squamous Cell Squamous Epithelium Stratified Squamous Epithelium Survival Rate System Time Transgenic Animals Transgenic Mice Transgenic Organisms Tumor Angiogenesis Tumor Cell Invasion Tumor Suppressor Genes Tumor stage Up-Regulation Uterus angiogenesis c-ets1 transcription factor cell growth insight keratinocyte lymph nodes malignant mouth neoplasm mouse model mouth squamous cell carcinoma neoplastic neoplastic cell novel novel strategies novel therapeutics oral cavity epithelium prevent programs research study tumor tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The oncogene Ets-1 is over-expressed in a large proportion of oral squamous cell cancers and expression of Ets- 1 is highly-correlated with tumor stage and the presence of lymph node metastases. Ets-1 is known to regulate the expression genes involved in tumor invasion and neo-angiogenesis, including matrix metalloproteases and endothelial cell growth factor receptors. In addition, Ets-1 has been implicated in controlling the expression of genes important for cell cycle progression and for regulating apoptosis. Finally, gene-targeted Ets-1 deficient mice demonstrate a role for Ets-1 in limiting cellular differentiation. Thus, Ets-1 may influence tumor progression in multiple ways by promoting invasion, angiogenesis and proliferation while at the same time limiting apoptosis and preventing terminal differentiation. To better define the precise roles of Ets-1 in oral tumor formation and progression, we have generated a transgenic mouse model system in which expression of Ets-1 can be induced in the differentiated cells of the oral epithelium. Upon Ets-1 induction, these mice exhibit dramatic changes in the epithelium including increased proliferation, blocked terminal differentiation and malignant conversion. We now propose to use this mouse model to identify the mechanisms by which Ets-1 regulates important pathways involved in oral cancer formation. These studies will be supplemented by complementary analyses using cultured oral keratinocytes. The results of our experiments will help to determine whether therapies directed against Ets-1 would be clinically useful in treating aggressive oral squamous cell carcinomas. Oral squamous cell carcinoma (OSCC) is a neoplasm that arises in the stratified squamous epithelium of the mouth. Five-year survival rates for patients with oral squamous cell cancers have not changed much in the last 20 years, suggesting that new approaches to therapy are needed. Our studies are designed to identify the role of the oncogene Ets-1 in regulating OSCC initiation and progression, with the eventual hope of developing novel strategies to target Ets-1 activity and regulate tumor cell growth.

描述（申请人提供）：癌基因Ets-1在大部分口腔鳞状细胞癌中过度表达，并且Ets-1的表达与肿瘤分期和淋巴结转移的存在高度相关。已知 Ets-1 可以调节参与肿瘤侵袭和新血管生成的表达基因，包括基质金属蛋白酶和内皮细胞生长因子受体。此外，Ets-1 还参与控制对细胞周期进程和调节细胞凋亡重要的基因的表达。最后，基因靶向 Ets-1 缺陷小鼠证明了 Ets-1 在限制细胞分化中的作用。因此，Ets-1可能通过促进侵袭、血管生成和增殖，同时限制细胞凋亡和防止终末分化，以多种方式影响肿瘤进展。为了更好地确定 Ets-1 在口腔肿瘤形成和进展中的精确作用，我们构建了转基因小鼠模型系统，其中可以在口腔上皮的分化细胞中诱导 Ets-1 的表达。在 Ets-1 诱导后，这些小鼠表现出上皮细胞的巨大变化，包括增殖增加、终末分化受阻和恶性转化。我们现在建议使用该小鼠模型来确定 Ets-1 调节口腔癌形成重要途径的机制。这些研究将通过使用培养的口腔角质形成细胞的补充分析来补充。我们的实验结果将有助于确定针对 Ets-1 的疗法是否在临床上可用于治疗侵袭性口腔鳞状细胞癌。口腔鳞状细胞癌（OSCC）是一种产生于口腔复层鳞状上皮的肿瘤。口腔鳞状细胞癌患者的五年生存率在过去 20 年中没有太大变化，这表明需要新的治疗方法。我们的研究旨在确定癌基因 Ets-1 在调节 OSCC 发生和进展中的作用，最终希望开发出针对 Ets-1 活性和调节肿瘤细胞生长的新策略。