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）是全球男性第五大常见癌症，也是癌症相关死亡的第二大原因。HCC的一个独特特征是它们经历肝内转移，导致对治疗无反应的侵袭性进展。HCC的发病率在美国呈上升趋势。显然，更好地理解HCC进展和耐药的机制对于设计有效的治疗方法将是重要的。目前的建议集中在叉头框转录因子FoxM 1，这是核心重要的肝癌进展。FoxM 1过表达是侵袭性HCC和预后不良的标志。在实验模型中，FoxM 1对HCC的发展和进展至关重要。肝脏中缺乏FoxM 1表达的小鼠不能发展HCC。此外，我们开发了一种双转基因株（FoxM 1bTg;Arf-/-）表达FoxM 1在其抑制剂，肿瘤抑制因子ARF的情况下，当受到肿瘤促进方案发展转移性肝癌。这种双转基因株为研究HCC的进展和转移提供了一种罕见的模型。最近的研究提供了肝癌干细胞（LCSCs）在HCC中的证据。它们的存在与致瘤性增加、复发、化疗耐药性和生存率低有关。在这项提议中，我们将寻找FoxM 1在LCSC存活中的作用的体内证据，并研究FoxM 1支持其存活和增殖的机制。我们将测试一个新的假设，即激活的Akt和FoxM 1合作驱动HCC的转移。此外，我们将使用我们的双转基因小鼠模型来研究小分子Akt抑制剂对HCC转移的影响。我们提供了基因证据表明，肿瘤抑制因子ARF抑制FoxM 1诱导的肝癌转移，并表征了来自小鼠ARF的足以抑制FoxM 1的19-aa肽。我们将检验ARF肽通过消除LCSC增加无复发生存率的假设。此外，我们还将确定ARF肽是否使HCC对索拉非尼敏感。目标是：1.研究FoxM 1支持肝癌干细胞的机制。2.确定FoxM 1激活Akt的机制，并研究激活的Akt是否与FoxM 1协同驱动侵袭性HCC进展。3.研究ARF衍生的FoxM 1肽抑制剂对LCSC和无复发生存的影响。现有的治疗方法对侵袭性HCC不起作用。有证据表明，FoxM 1的抑制阻断了侵袭性HCC的进展。显然，更深入地了解FoxM 1通路在HCC进展中的作用将有助于开发有效治疗该疾病的新治疗方法。