Genetic Approaches to Pancreatic Cancer Progression

项目摘要/摘要 转移性胰腺癌是一种致命的疾病。遗传和表观遗传的改变 胰腺癌发展和进展背后的分子信号传导变化仍不清楚。我们 最近的研究表明，FoxM 1蛋白表达在原发性胰腺癌中显著增加， 与正常胰腺组织相比，同样，人胰腺癌细胞 表现出FoxM 1表达的显著增加。胰腺癌细胞FoxM 1表达水平的研究 与转移潜能直接相关。基因工程过表达FoxM 1促进了 人胰腺癌在异种移植模型中的生长和转移，而FoxM 1敲低则可以抑制胰腺癌的生长和转移。 对生重要的是，小鼠胰腺中KLF 4的特异性消融导致FoxM 1过表达。 FoxM 1的过度表达和KLF 4的低表达在胰腺癌中是明显的。 L-KrasG 12 D/+; pdx 1-cre+小鼠。我们假设，肿瘤抑制基因和表观遗传学的变化， 癌基因和随后的FoxM 1信号转导的改变严重影响胰腺癌的发展 和进步。 为了验证我们的假设，我们提出了以下三个具体目标：1。确定FoxM 1的因果作用 使用基因工程小鼠模型研究胰腺癌发展和进展的信号传导。我们 FoxM 1的过度表达是激活Kras介导的胰腺癌的关键事件。 因此，基因减少或缺失FoxM 1将减弱K-ras介导的胰腺癌发生。 致癌作用2.确定KLF 4缺失与Kras癌基因激活的因果关系 胰腺癌的发展和进展。我们将测试我们的假设，延迟发作或缺乏 在KLF 4缺失或激活的Kras小鼠模型中，侵袭性癌症可能需要获得额外的遗传学标记， 和/或表观遗传学改变，KLF 4的缺失可能与Kras的激活协同作用，从而减少 KLF 4基因的缺失或缺失可能促进Kras介导的胰腺癌发生。3.确定 KLF 4功能丧失与FoxM 1表达和功能失调之间的机制关系 胰腺上皮细胞我们将检验我们的假设，即KLF 4在转录水平上抑制 FoxM 1;胰腺癌发生过程中KLF 4的缺失导致FoxM 1的过度表达;因此遗传 FoxM 1基因的缺失可逆转KLF 4基因敲除小鼠胰腺癌前病变和恶性表型。 这三个具体目标得到了我们各自初步数据的支持，可以独立进行检验 利用我们独特的研究资源，但它们高度相关，相互支持。我们预测 这些研究的完成将为以下方面的分子和遗传基础提供有见地的信息： 胰腺癌的发病机制，并确定分子靶点，以设计有效的预防和 治疗策略从长远来看，我们的研究也可以导致进一步的分子研究， 机制介导FoxM 1信号转导失调及其与ras和KLF 4通路的串扰。

Project Abstract/Summary Metastatic pancreatic cancer is a lethal disease. The genetic and epigenetic alterations and consequent changes in molecular signaling behind pancreatic cancer development and progression remain unclear. Our recent studies have shown that FoxM1 protein expression is drastically increased in primary pancreatic cancers when compared with that in normal pancreatic tissue. Consistently, human pancreatic cancer cells exhibit a substantial increase in FoxM1 expression. The levels of FoxM1 expression in pancreatic cancer cells directly correlate with metastatic potential. Genetically engineered overexpression of FoxM1 promotes the growth and metastasis of human pancreatic cancer in xenograft models, while FoxM1 knockdown does the opposite. Importantly, specific ablation of KLF4 in the pancreas of mice results in FoxM1 overexpression. Drastic FoxM1 overexpression and KLF4 underexpression are evident in pancreatic tumors developed in L-KrasG12D/+;pdx1-cre+ mice. We postulate that genetic and epigenetic changes of tumor suppressors and oncogenes and consequent alterations of FoxM1 signaling critically impact pancreatic cancer development and progression. To test our hypothesis, we propose the following three specific aims: 1. Determine the causal role of FoxM1 signaling in pancreatic cancer development and progression using genetically engineered mouse models. We will test our hypothesis that overexpression of FoxM1 is a critical event in activated Kras-mediated pancreatic carcinogenesis; thus genetic reduction or deletion FoxM1 will attenuate K-ras-mediated pancreatic carcinogenesis. 2. Determine the casual cooperation of loss of KLF4 and activation of Kras oncogene in pancreatic cancer development and progression. We will test our hypothesis that delayed onset or absence of invasive cancer in KLF4-null or activated Kras mouse models may require acquisition of additional genetic and/or epigenetic alterations and that a loss of KLF4 may cooperate with an activation of Kras; thus reduction or deletion of KLF4 in mouse should promote Kras-mediated pancreatic carcinogenesis. 3. Determine the mechanistic relationship between loss of KLF4 function and dysregulated FoxM1 expression and function in pancreatic epithelial cells. We will test our hypothesis that KLF4 transcriptionally represses the expression of FoxM1; loss of KLF4 during carcinogenesis of pancreas leads to overexpression of FoxM1; thus genetic deletion of FoxM1 will reverse the premalignant and malignant phenotypes of pancreas in KLF4-null mouse. These three specific aims are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. We predict that completion of these studies will provide insightful information for the molecular and genetic basis of pancreatic cancer pathogenesis and for identification of molecular targets to design effective preventive and therapeutic strategies. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated FoxM1 signaling and its crosstalk with ras and KLF4 pathways.