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.

项目概要 肝细胞癌（HCC）是全世界最致命的癌症之一。通常，该疾病是在 对现有疗法有抵抗力的高级癌症进展的晚期阶段。肝癌也是一个重要的 退伍军人之间的问题。根据 VA Research Currents（Mike Richman，2017 年，VA 网站）的展望 美国退伍军人中肝细胞癌的发病率不容乐观，其增长速度约为五倍 高于美国一般人口。 2015 年的一项研究表明，美国退伍军人中的 HCC 发病率在 2021 年。显然，更好地了解 HCC 的分子机制将非常重要 制定有效的治疗策略。本提案重点关注叉头盒M1（FoxM1） 基因，因为它对于 HCC 的发生和进展至关重要。此外，FoxM1 在 HCC 中过度表达 预示预后不良。 FoxM1 作为参与增殖的基因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 研究假设是新发现的 FoxM1 的抑制功能在 HCC 的发生和进展。 我们使用 Ras 转基因模型来治疗 HCC，主要是因为 Ras 通路在 HCC 中普遍被激活。 通过其调节因子的表观遗传沉默来抑制人类肝癌。使用该模型，我们证明了条件删除 HCC 发展后 FoxM1 的表达会导致肝癌干细胞 (LCSC) 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 家族蛋白的相互作用，发生在细胞周期的 G1 期。我们将调查 假设 FoxM1 的 G1 期抑制对于 FoxM1 支持的机制很重要 肝癌干细胞。我们开发了一种表达突变型 FoxM1 的新型敲入小鼠品系 抑制功能缺陷，但保留其激活转录的能力。该菌株将用于 研究抑制功能在肝癌发生和肝癌干细胞中的意义。在 此外，使用该敲入小鼠品系，我们将确定 FoxM1 的抑制功能是否是 对于慢性肝损伤的恢复很重要。具体目标是： 1. 研究FoxM1对肝癌干细胞G1期的抑制作用。 2. 研究FoxM1在HCC发生和进展中的抑制功能。 3. 探讨FoxM1的抑制功能对于慢性肝病的恢复是否重要 受伤。