FoxM1 in tumor cell

项目摘要 FOXM1是一个叉头盒家族转录因子，在广泛的 多种人类癌症，包括肝癌、结肠癌、肺癌和前列腺癌。一切都结束了- 前列腺癌组织中的表达与转移有关。在小鼠模型中，FOXM1是 对肝癌的发生是必不可少的，对肿瘤的进展也是必需的。为 例如，由肿瘤抑制因子衍生的多肽对FOXM1的特异性抑制 P19Arf，导致小鼠肝脏肿瘤的消退，提示FOXM1在 肿瘤细胞的存活。此外，几项研究表明FOXM1是一种潜在的抗癌药物 毒品目标。然而，FOXM1参与肿瘤发生的机制 并促进肿瘤细胞存活尚不清楚。在这份提案中，我们计划调查 新发现的FOXM1在转化和肿瘤细胞存活中的作用 FOXM1作为抗肿瘤药物靶点的考虑将具有重要意义 耐药肿瘤。 我们观察到FOXM1被活性氧物种(ROS)激活，并且 致癌RAS激活需要ROS的FOXM1。此外，我们还获得了证据，证明 上调的FOXM1下调ROS的负反馈机制 调节ROS。负反馈环对体内增殖细胞的存活至关重要 存在过多的ROS。FOXM1通过下调促进肿瘤细胞存活 调节ROS水平。我们计划调查FOXM1是 ROS在增殖细胞和肿瘤细胞中的关键调节因子，而肿瘤细胞 表达ROS诱导癌基因的人对FOXM1上瘾。此外，我们还将 确定FOXM1在肿瘤细胞中的过表达是否使其对 通过下调ROS进行治疗。这些研究将确定FOXM1的功能 在肿瘤的发展和进展中，以及建立FOXM1在 在耐药发展过程中的表达。

Project Summary FoxM1 is a forkhead-box family transcription factor that is over-expressed in a wide variety of human cancers, including cancers of liver, colon, lung and prostate. Its over- expression in prostate cancers correlates with metastasis. In mouse models, FoxM1 is essential for development liver carcinomas, and is required for tumor progression. For example, specific inhibition of FoxM1, by a peptide derived from the tumor suppressor p19Arf, causes regression of liver tumors in mice, suggesting a critical role for FoxM1 in survival of tumor cells. Also, several studies implicated FoxM1 as a potential anticancer drug target. However, the mechanisms by which FoxM1 participates in tumorigenesis and promotes survival of tumor cells are not clear. In this proposal, we plan to investigate a newly discovered function of FoxM1 in transformation and tumor cell survival, which will be significant in the considerations of FoxM1 as an anti-tumor drug target in drug resistant tumors. We observed that FoxM1 is activated by reactive oxygen species (ROS), and that oncogenic Ras activates FoxM1 requiring ROS. Moreover, we obtained evidence for a negative feed back mechanism for regulation of ROS in which the elevated FoxM1 down regulates ROS. The negative feed back loop is critical for survival of proliferating cells in the presence of excessive ROS. FoxM1 promotes survival of tumor cells by down regulating the levels of ROS. We plan to investigate the hypotheses that FoxM1 is the pivotal regulator of ROS in proliferating cells and in tumor cells, and that the tumors cells expressing ROS-inducing oncogenes are "addicted" to FoxM1. Moreover, we will determine whether over expression of FoxM1 in tumor cells confers resistance to therapies by down regulating ROS. These studies will establish the functions of FoxM1 in tumor development and progression, as well as establish a role of FoxM1 over expression in the development of drug resistance.