FoxM1 in liver cancer.

描述（由申请人提供）：肝细胞癌（HCC）是全球第五大常见癌症，也是男性癌症相关死亡的第二大原因。hcc的一个独特特征是它们会发生肝内转移，导致侵袭性进展，对治疗没有反应。HCC的发病率在美国呈上升趋势。显然，更好地了解HCC进展和耐药的机制对于设计有效的治疗方法至关重要。目前的建议集中在叉头盒转录因子FoxM1上，它对HCC的进展至关重要。FoxM1过表达是侵袭性HCC和预后不良的标志。在实验模型中，FoxM1对HCC的发生和发展至关重要。肝脏中缺乏FoxM1表达的小鼠不能发生HCC。此外，我们开发了一种双转基因菌株（FoxM1bTg;Arf-/-），在缺乏FoxM1抑制剂（肿瘤抑制因子Arf）的情况下表达FoxM1，当受到肿瘤促进方案时发生转移性HCC。这种双转基因菌株为研究HCC的进展和转移提供了一种罕见的模型。最近的研究为肝癌干细胞（LCSCs）在HCC中的作用提供了证据。它们的存在与增加的致瘤性、复发、化疗耐药和较差的生存率有关。在本研究中，我们将寻找FoxM1在LCSCs存活中作用的体内证据，并研究FoxM1支持LCSCs存活和增殖的机制。我们将验证激活Akt和FoxM1共同驱动HCC转移的新假设。同时，我们将利用我们的双转基因小鼠模型研究小分子akt -抑制剂对HCC转移的影响。我们提供了肿瘤抑制因子ARF抑制FoxM1诱导的HCC转移的遗传学证据，并鉴定了来自小鼠ARF的19-aa肽足以抑制FoxM1。我们将检验arf肽通过消除LCSCs增加无复发生存的假设。此外，我们将确定arf肽是否使HCC对索拉非尼敏感。目标是：1。研究FoxM1支持肝癌干细胞的机制。2. 确定FoxM1激活Akt的机制，并研究激活的Akt是否与FoxM1协同驱动侵袭性HCC进展。3. 探讨arf衍生的FoxM1肽抑制剂对LCSCs和无复发生存的影响。现有的治疗方法对侵袭性HCC无效。有证据表明FoxM1的抑制可以阻断HCC的侵袭性进展。显然，更深入地了解foxm1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。

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.