FoxM1 in tumor cell

肿瘤细胞中的 FoxM1

• 批准号: 10004294
• 负责人: Pradip Raychaudhuri
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004294
• 关键词: Antineoplastic Agents; Binding; CRISPR/Cas technology; Cell Cycle; Cell Therapy; Chronic; Clinic; Development; Diagnosis; Differentiated Gene; Disease; Drug resistance; Epigenetic Process; G1 Phase; Generations; Genes; Genetic Recombination; Genetic Transcription; Head; Hepatocyte; Human; Hybrids; Injury; Knock-in Mouse; Link; Liver; Liver Regeneration; Maintenance; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Molecular; Mouse Strains; Mus; Neoplasm Metastasis; Pathway interactions; Phosphorylation; Play; Population; Primary carcinoma of the liver cells; Protein Family; Recovery; Repression; Research; Resistance; Role; Site; Testing; Therapeutic; Time; Transcriptional Activation; Transgenic Model; Transplantation; Treatment Efficacy; Veterans; base; cancer cell; cancer stem cell; chronic liver disease; chronic liver injury; liver function; mimetics; mutant; neoplastic cell; novel; outcome forecast; overexpression; pluripotency; stem; stem-like cell; tumor progression; web site

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.

项目摘要 肝细胞癌（HCC）是世界上最致命的癌症之一。通常这种疾病是在 对现有疗法有抵抗力的晚期高级别癌症进展。HCC也是一个重要的 退伍军人的问题。根据VA Research Currents（Mike Richman，2017年，VA网站）， 美国退伍军人中肝细胞癌的发病率是暗淡的，因为它以大约五倍的速度增长， 比一般的美国人。2015年的一项研究表明，美国退伍军人中的肝癌发病率在2015年达到顶峰 2021年。显然，深入了解HCC的分子机制是非常重要的 用于开发有效的治疗策略。本方案重点介绍叉头箱M1（FoxM1） 基因，因为它对HCC的发展和进展至关重要。此外，FoxM1在HCC中的过表达 预示预后不良。FoxM1作为参与增殖的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 研究的假设是，新发现的FoxM1的抑制功能在人类免疫系统中起着关键作用。 HCC的发生和发展。 我们正在使用Ras转基因肝癌模型，主要是因为Ras通路在肝癌细胞中普遍被激活。 通过表观遗传学沉默其调节因子的人HCC。利用这个模型，我们证明了条件删除 肝癌发展后FoxM1的表达导致肝癌干细胞（LCSC）的优先损失。有趣的是， 我们观察到FoxM1抑制肝分化基因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。我们将调查 FoxM1的G1期抑制对于FoxM1支持细胞凋亡的机制是重要的， 肝癌干细胞我们已经开发了一种新的基因敲入小鼠品系，其表达突变型FoxM1 缺乏抑制功能，但保留了激活转录的能力。该菌株将用于 探讨其在肝癌发生发展及肝癌干细胞中的意义。在 此外，使用该基因敲入小鼠品系，我们将确定FoxM1的阻遏功能是否是 对慢性肝损伤的恢复很重要。具体目标是： 1.探讨FoxM1在肝癌干细胞维持中的G1期抑制作用。 2.探讨FoxM1在肝癌发生发展中的抑制作用。 3.研究FoxM1的抑制功能是否对慢性肝病的恢复很重要 损伤