FoxM1 in tumor cell

项目总结 肝细胞癌是世界上最致命的癌症之一。通常情况下，这种疾病是在 对现有治疗方法有抵抗力的高级别癌症进展的晚期。肝细胞癌也是一个重要的 退伍军人中的问题。根据VA Research Current(Mike Richman，2017，VA网站)的说法，前景 对于美国退伍军人中的肝细胞癌来说是黯淡的，因为它正在以大约五倍的速度增长 比一般美国人的人数还要多。2015年的一项研究表明，美国退伍军人中的肝癌将在 2021年。显然，更好地理解肝癌的分子机制将是重要的。 用于开发有效的治疗策略。本提案的重点是叉头箱M1(FOXM1) 因为它对肝细胞癌的发生和发展是必不可少的。FOXM1在肝细胞癌中的过度表达 预示着不良的预后。FOXM1作为增殖相关基因的激活剂已被广泛研究， 多能性和转移。最近，我们发现了FOXM1的抑制功能。在本提案中，我们将 调查假说是，新发现的FOXM1的抑制功能在 肝细胞癌的发生发展。 我们正在使用RAS转基因肝癌模型，主要是因为RAS途径在肝癌中普遍激活 人类肝癌通过其调控因子的表观遗传沉默。使用该模型，我们证明了条件删除 肝癌发生后FOXM1的表达导致肝癌干细胞(LSCs)优先丢失。有趣的是， 我们观察到FOXM1抑制肝脏分化基因FOXA2。FOXM1对FOXA2的抑制涉及 FOXM1与RB家族蛋白相互作用，发生在细胞周期的G1期。我们会调查的 假设FOXM1的G1期抑制对FOXM1支持FXM1的机制很重要 肝癌干细胞。我们已经开发出一种新的敲入小鼠品系，它表达突变的FOXM1 缺乏抑制功能，但仍有激活转录的能力。这种菌株将被用来 探讨抑制功能在肝癌发生发展和肝癌干细胞中的意义。在……里面 此外，使用该敲入鼠品系，我们将确定FOXM1的抑制功能是否为 对慢性肝损伤的恢复很重要。具体目标是： 1.研究FOXM1在肝癌干细胞维持中的G1期抑制作用。 2.探讨FOXM1在肝细胞癌发生发展中的抑制作用。 3.研究FOXM1的抑制功能对慢性肝脏的康复是否重要 受伤。

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Often the disease is diagnosed at a late stage of high-grade cancer progression that is resistant to the available therapies. HCC is also a significant problem among the Veterans. According to VA Research Currents (Mike Richman, 2017, VA website) the outlook for hepatocellular carcinoma among the US Veterans is bleak, as it is increasing at a rate about five times greater than that of general US population. A 2015 study indicated that HCC among US Veterans is going peak in the year of 2021. Clearly, a greater understanding of the molecular mechanisms underlying HCC will be important for development of efficacious therapeutic strategies. This proposal focuses on the fork-head box M1 (FoxM1) gene because it is essential for HCC development and progression. Also, overexpression of FoxM1 in HCC predicts poor prognosis. FoxM1 has been extensively studied as an activator of genes involved in proliferation, pluripotency, and metastasis. Recently, we discovered a repression function of FoxM1. In this proposal we will investigate the hypothesis is that the newly discovered repression function of FoxM1 plays critical roles in the development and progression of HCC. We are using a Ras-transgenic model for HCC, mainly because the Ras-pathway is ubiquitously activated in human HCC through epigenetic silencing of its regulators. Using that model, we showed that conditional deletion of FoxM1 after HCC development causes preferential loss of the liver cancer stem cells (LCSCs). Interestingly, we observed that FoxM1 represses the liver differentiation gene FoxA2. Repression of FoxA2 by FoxM1 involves interactions of FoxM1 with the Rb-family proteins, and it occurs in G1 phase of the cell cycle. We will investigate the hypothesis that G1 phase repression of FoxM1 is important for the mechanism by which FoxM1 supports the liver cancer stem cells. We have developed a novel knock-in mouse strain that expresses a mutant FoxM1 deficient in the repression function, but retains its ability to activate transcription. That strain will be used to investigate the significance of the repression function in liver cancer development and liver cancer stem cells. In addition, using that knock-in mouse strain, we will determine whether the repression function of FoxM1 is important for recovery from chronic liver injury. The specific aims are: 1. Investigate the G1 phase repression function of FoxM1 in maintenance of the liver cancer stem cells. 2. Investigate the repression function of FoxM1 in HCC development and progression. 3. Investigate whether the repression function of FoxM1 is important for recovery from chronic liver injury.