FoxM1 in liver cancer.

FoxM1 在肝癌中的作用。

• 批准号: 8787994
• 负责人: Pradip Raychaudhuri
• 金额: $ 40.51万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787994
• 关键词: Apoptosis; BAY 54-9085; Boxing; Cancer Etiology; Cells; Cessation of life; Development; Disease; Disease Resistance; Experimental Models; Fibrosis; Genes; Genetic; Goals; Health; Human; Incidence; Lead; Liver; Malignant Epithelial Cell; Malignant neoplasm of liver; Metastatic Neoplasm to the Liver; Modeling; Mus; Neoplasm Metastasis; Pathway interactions; Peptides; Population; Primary carcinoma of the liver cells; Protocols documentation; Reactive Oxygen Species; Recurrence; Recurrent disease; Regulation; Resistance; Role; Second Primary Cancers; Stem cells; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor Promotion; Tumor Suppressor Proteins; Tumorigenicity; Work; base; cancer stem cell; combat; design; in vivo; inhibitor/antagonist; insight; men; mouse model; novel; novel therapeutic intervention; outcome forecast; small molecule; therapy resistant; transcription factor; tumor

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer- related death in men worldwide. A unique feature of HCCs is that they undergo intra-hepatic metastasis, causing aggressive progression that does not respond to therapy. The incidences of HCC are on the rise in the US. Clearly, a better understanding of the mechanisms underlying progression and resistance of HCC will be important in designing efficacious therapeutic approaches. The current proposal focuses on the forkhead box transcription factor FoxM1, which is centrally important for HCC progression. FoxM1 over-expression is a marker for aggressive HCC and poor prognosis. In experimental models, FoxM1 is essential for HCC development and progression. Mice lacking FoxM1 expression in the liver fail to develop HCC. Moreover, we developed a bi-transgenic strain (FoxM1bTg;Arf-/-) expressing FoxM1 in the absence of its inhibitor, the tumor suppressor ARF, when subjected to a tumor promotion protocol develops metastatic HCC. This bi-transgenic strain offers a rare model to study progression and metastasis of HCC. Recent studies provided evidence for liver cancer stem cells (LCSCs) in HCC. Their presence is associated with increased tumorigenicity, recurrence, chemoresistance, and poor survival. In this proposal, we will seek in vivo evidence for a role of FoxM1 in the survival of the LCSCs, and investigate the mechanisms by which FoxM1 support their survival and proliferation. We will test a novel hypothesis that activated Akt and FoxM1 collaborate to drive metastasis of HCC. Also, we will use our bi-transgenic mouse model to investigate effects of small molecule Akt-inhibitor on HCC metastasis. We provided genetic evidence that the tumor suppressor ARF inhibits FoxM1-induced metastasis of HCC, and characterized a 19-aa peptide derived from mouse ARF that is sufficient to inhibit FoxM1. We will test the hypothesis that the ARF-peptide, by eliminating the LCSCs, increases recurrence-free survival. Also, we will determine whether the ARF-peptide sensitizes HCC to sorafenib. The aims are: 1. Investigate the mechanisms by which FoxM1 supports the liver cancer stem cells. 2. Determine the mechanism by which FoxM1 activates Akt and investigate whether activated Akt collaborates with FoxM1 to drive aggressive HCC progression. 3. Investigate the effects of the ARF-derived peptide inhibitor of FoxM1 on the LCSCs and on recurrence-free survival. The available therapies do not work for aggressive HCC. There is evidence that inhibition of FoxM1 blocks aggressive HCC progression. Clearly, a deeper understanding of the FoxM1-pathways that define its role in HCC progression will aid in developing new therapeutic approaches that are effective in treating the disease.

描述（由申请人提供）：肝细胞癌（HCC）是全世界男性癌症与癌症相关死亡的第二大癌症和第二大主要原因。 HCC的一个独特特征是它们经历了肝内转移，导致积极进展，对治疗没有反应。 HCC的发生率在美国正在上升。显然，对HCC进展和抵抗力的机制的更好理解对于设计有效的治疗方法至关重要。当前的提案着重于叉子盒转录因子FOXM1，这对于HCC进展至关重要。 FOXM1过表达是侵略性HCC和预后不良的标志物。在实验模型中，FOXM1对于HCC开发和进展至关重要。缺乏FOXM1表达的小鼠无法发展HCC。此外，在接受肿瘤抑制剂ARF的情况下，我们开发了表达FOXM1的双重转基因菌株（FOXM1BTG; ARF - / - ），当经受肿瘤促进方案时会产生转移性HCC。这种双重转基因菌株为研究HCC的进展和转移提供了罕见的模型。最近的研究提供了HCC中肝癌干细胞（LCSC）的证据。它们的存在与肿瘤性，复发性，化学抗性和存活不良有关。在该提案中，我们将寻求体内证据证明FOXM1在LCSC的生存中的作用，并研究FOXM1支持其生存和增殖的机制。我们将测试一个新的假设，该假设激活了AKT和FOXM1，以驱动HCC转移。此外，我们将使用双重转基因小鼠模型来研究小分子Akt抑制剂对HCC转移的影响。我们提供了遗传证据，表明肿瘤抑制ARF抑制FOXM1诱导的HCC转移，并表征了源自小鼠ARF的19-AA肽，足以抑制FOXM1。我们将检验以下假设：ARF肽通过消除LCSC会增加无复发的存活率。另外，我们将确定ARF肽是否将HCC敏感到索拉非尼。目的是：1。研究FOXM1支持肝癌干细胞的机制。 2。确定FOXM1激活AKT的机制，并研究激活AKT是否与FOXM1合作以驱动侵略性HCC进展。 3。研究FOXM1的ARF衍生肽抑制剂对LCSC和无复发生存的影响。可用的疗法不适用于激进的HCC。有证据表明，FOXM1的抑制阻碍了侵略性的HCC进展。显然，对定义其在HCC进展中作用的FOXM1轨道的更深入了解将有助于开发有效治疗该疾病的新治疗方法。