Functional Validation of Pancreatic Cancer Progression Biomarker

项目摘要/摘要 转移性胰腺癌是一种致命的疾病。基因和表观遗传的改变和 胰腺癌发生发展过程中分子信号转导的变化 目前仍不清楚。进展生物标记物的功能鉴定和验证对于 胰腺癌的诊断和治疗。最近的研究表明，这种异常 WNT/β-连环蛋白途径在胰腺癌细胞中的激活在细胞内发挥重要作用 增殖、侵袭和转移。-连环蛋白的稳定性和核转位是一种 导致胰腺癌恶性表型的关键步骤。我们最近的研究也有 研究表明，转录因子FOXM1对细胞的增殖、侵袭和 人胰腺癌的致瘤性。重要的是，我们的研究表明，FOXM1和 β-连环蛋白在胰腺癌中的生理和功能相关性 细胞。 以前的研究包括我们自己的研究足以让我们相信相互作用 FOXM1和β-catenin信号转导在胰腺癌的发生和发展中起关键作用 进步。为了验证我们的假设，我们设计了几组有组织的实验 围绕三个具有明确目标的具体目标。目标1将决定FOXM1是否与 与-连环蛋白结合并促进其核转位；目标2将定义 β-连环蛋白/FOXM1在胰腺癌侵袭转移中的作用 β-连环蛋白和FOXM1在胰腺癌组织中的表达及其临床意义 在人胰腺癌发病机制中的意义。因此，我们的研究整合了三个层面的 功能验证研究：分子生物学、细胞生物学和临床组织病理学。 我们建议的研究的完成将代表着我们在理解上的重大进步 连环蛋白和FOXM1基因表达及功能异常的深层次机制 尤其是在胰腺癌的发生和发展中。因此，我们建议的研究是 理解连环蛋白信号和FOXM1之间的相互作用至关重要 信号转导及其功能对胰腺癌生物学的影响及其临床应用价值 设计有效手段控制胰腺癌细胞生长、侵袭的分子靶点 和转移。从长远来看，我们的研究也可以导致对分子的进一步研究 Wnt/β-catenin信号失控的机制及其与FoxM1信号通路的串扰 将我们的发现转化为临床患者护理是我们的另一个长期目标。

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. Functional identification and validation of progression biomarkers is essential for pancreatic cancer diagnosis and treatment. Recent studies indicated that the aberrant Wnt/¿-catenin pathway activation in pancreatic cancer cells play an important role in cell proliferation, invasion, and metastasis. Stability and nuclear translocation of ¿-catenin protein is a critical step leading to malignant phenotype of pancreatic cancer. Our recent studies also have shown that transcription factor FoxM1 critically contributes to cell proliferation, invasion and tumorigenicity of human pancreatic cancer. Importantly, our studies have shown that FoxM1 and ¿-catenin appears to be associated with each other physically and functionally in pancreatic cancer cells. The prior studies including our own are sufficient to make us believe that the interactions between FoxM1 and ¿-catenin signaling play a critical role in pancreatic cancer development and progression. To test our hypothesis, we have designed several sets of experiments organized around three specific aims with well-defined goals. Aim 1 will determine whether FoxM1 interacts with ¿-catenin and promotes its nuclear translocation; Aim 2 will define the role of the interaction of ¿-catenin/FoxM1 in pancreatic tumor invasion and metastasis; and Aim 3 will to determine the expression of ¿-catenin and FoxM1 in pancreatic cancer tissues and delineate their clinical significance in human pancreatic cancer pathogenesis. Thus, our studies integrate three levels of functional validating investigation: molecular biology, cell biology, and clinicohistopathology. Completion of our proposed studies will represents a substantial advance in our understanding the in-depth mechanism of dysregulated ¿-catenin and FoxM1 expression and function in general and in pancreatic cancer development and progression in particular. Thus, our proposed studies are fundamentally important to understand the interaction between ¿-catenin signaling and FoxM1 signaling and its function impact on pancreatic cancer biology and to determine its value as a molecular target for designing effective modality to control pancreatic cancer cell growth, invasion and metastasis. In the long term, our study also can lead to further investigation of the molecular mechanisms mediating disregulated Wnt/¿-Catenin signaling and its crosstalk with FoxM1pathway. Translation of our findings into clinical patient care is another long-term goal of ours.