Ets-1 Expression in Squamous Cells of the Oral Cavity

描述（由申请人提供）：癌基因Ets-1在很大比例的口腔鳞状细胞癌中过表达，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阻止终末分化，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可以在口腔上皮分化细胞中被诱导表达。经Ets-1诱导后，这些小鼠的上皮发生了显著变化，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种小鼠模型来确定Ets-1调节口腔癌形成的重要途径的机制。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的疗法是否在临床治疗侵袭性口腔鳞状细胞癌中有用。

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.