Ets-1 Expression in Squamous Cells of the Oral Cavity

描述（由申请人提供）：癌基因Ets-1在大部分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调节参与肿瘤侵袭和新血管生成的基因的表达，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。为了更好地定义Ets-1在口腔肿瘤形成和进展中的确切作用，我们已经产生了一种转基因小鼠模型系统，其中Ets-1的表达可以在口腔上皮的分化细胞中诱导。在Ets-1诱导后，这些小鼠表现出上皮细胞的显著变化，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的补充分析来补充。我们的实验结果将有助于确定是否针对Ets-1的疗法将在临床上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发生和发展中的作用，最终希望开发新的策略来靶向Ets-1活性并调节肿瘤细胞生长。

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.