Ets-1 Expression in Squamous Cells of the Oral Cavity

口腔鳞状细胞中 Ets-1 的表达

• 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
• 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

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有无淋巴结转移高度相关。已知Ets-1调控肿瘤侵袭和新生血管生成相关基因的表达，包括基质金属蛋白酶和内皮细胞生长因子受体。此外，Ets-1还参与控制细胞周期进程和调节细胞凋亡的重要基因的表达。最后，基因靶向的Ets-1缺陷小鼠展示了Ets-1在限制细胞分化中的作用。因此，Ets-1可能通过促进肿瘤的侵袭、血管生成和增殖，同时限制细胞凋亡和阻止终末分化，从而影响肿瘤的进展。为了更好地确定Ets-1在口腔肿瘤形成和发展中的确切作用，我们建立了一个转基因小鼠模型系统，在该系统中，Ets-1可以在口腔上皮细胞的分化细胞中诱导表达。在Ets-1诱导后，这些小鼠的上皮细胞发生了戏剧性的变化，包括增殖增加，终末分化受阻和恶性转化。我们现在建议使用这个小鼠模型来确定ETS-1调控口腔癌形成的重要途径的机制。这些研究将通过对培养的口腔角质形成细胞进行补充分析来补充。我们的实验结果将有助于确定针对ETS-1的治疗是否在临床上用于治疗侵袭性口腔鳞癌。 口腔鳞状细胞癌(OSCC)是一种发生在口腔复层鳞状上皮的肿瘤。口腔鳞状细胞癌患者的五年存活率在过去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在调控口腔鳞癌发生和发展中的作用，最终希望开发针对Ets-1活性和调节肿瘤细胞生长的新策略。