FoxM1 in liver cancer.

描述(申请人提供)：肝细胞癌是全球第五大常见癌症，也是导致男性癌症相关死亡的第二大原因。肝细胞癌的一个独特特征是它们会发生肝内转移，导致对治疗没有反应的侵袭性进展。在美国，肝癌的发病率呈上升趋势。显然，更好地了解肝癌进展和耐药的潜在机制对于设计有效的治疗方法将是重要的。目前的研究重点是叉头盒转录因子FOXM1，它对肝细胞癌的进展起着至关重要的作用。FOXM1的过度表达是侵袭性肝细胞癌和预后不良的标志。在实验模型中，FOXM1在肝细胞癌的发生和发展中起着至关重要的作用。在肝脏中缺乏FOXM1表达的小鼠不会发生肝细胞癌。此外，我们开发了一种双转基因菌株(FoxM1bTg；Arf-/-)，在缺乏其抑制物肿瘤抑制因子ARF的情况下表达FOXM1，当受到肿瘤促进方案时会发生转移性肝癌。该双转基因株为研究肝细胞癌的进展和转移提供了一种难得的模型。最近的研究为肝癌中存在肝癌干细胞(LSCs)提供了证据。它们的存在与肿瘤的致瘤性、复发率、化疗耐药性和低存活率有关。在这个方案中，我们将寻找FOXM1在LC存活中的作用的体内证据，并研究FOXM1支持其存活和增殖的机制。我们将检验一种新的假说，即激活Akt和FOXM1共同推动肝癌的转移。此外，我们还将使用我们的双转基因小鼠模型来研究小分子Akt抑制物在肝癌转移中的作用。我们提供了肿瘤抑制因子ARF抑制FOXM1诱导的肝癌转移的遗传学证据，并鉴定了从小鼠ARF中提取的足以抑制FOXM1的19-AA多肽。我们将检验这一假设，即ARF多肽通过消除LSCs，增加无复发生存率。此外，我们还将确定ARF多肽是否使肝癌对索拉非尼敏感。研究目的：1.探讨FOXM1对肝癌干细胞的支持机制。2.确定FOXM1激活Akt的机制，并研究激活的Akt是否与FOXM1协同推动侵袭性肝癌的进展。3.研究ARF衍生的FOXM1多肽抑制剂对小鼠LC-SCs的作用及对无复发生存率的影响。现有的治疗方法对侵袭性肝癌不起作用。有证据表明，抑制FOXM1可以阻止侵袭性的肝癌进展。显然，对FOXM1-通路的深入了解将有助于开发有效治疗该疾病的新的治疗方法。

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.