Functional Validation of Pancreatic Cancer Progression Biomarker

描述（由申请人提供）：转移性胰腺癌是一种致命疾病。胰腺癌发生和发展背后的遗传和表观遗传改变以及随之而来的分子信号变化尚不清楚。进展生物标志物的功能鉴定和验证对于胰腺癌的诊断和治疗至关重要。近年来的研究表明，胰腺癌细胞中Wnt/b-catenin通路的异常激活在细胞增殖、侵袭和转移中起着重要作用。b-连环蛋白的稳定性和核易位是导致胰腺癌恶性表型的关键步骤。我们最近的研究也表明转录因子FoxM1在人胰腺癌的细胞增殖、侵袭和致瘤性中起重要作用。重要的是，我们的研究表明FoxM1和b-catenin在胰腺癌细胞中似乎在身体和功能上相互关联。包括我们自己在内的前期研究足以让我们相信FoxM1和b-catenin信号传导之间的相互作用在胰腺癌的发生和发展中起着关键作用。为了验证我们的假设，我们围绕三个明确的目标设计了几组实验。Aim 1将确定FoxM1是否与b-连环蛋白相互作用并促进其核易位；目的2将确定b-catenin/FoxM1相互作用在胰腺肿瘤侵袭和转移中的作用；和Aim 3将确定b-catenin和FoxM1在胰腺癌组织中的表达，并描述它们在人类胰腺癌发病机制中的临床意义。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。我们所提出的研究的完成将代表我们对b-catenin和FoxM1表达和功能失调的深入机制的理解取得实质性进展，特别是在胰腺癌的发生和进展中。因此，我们所提出的研究对于理解b-catenin信号传导与FoxM1信号传导之间的相互作用及其对胰腺癌生物学的功能影响，以及确定其作为设计有效控制胰腺癌细胞生长、侵袭和转移模式的分子靶点的价值具有重要意义。从长远来看，我们的研究还可以进一步研究介导Wnt/b-Catenin信号失调的分子机制及其与foxm1通路的串扰。将我们的发现转化为临床病人护理是我们的另一个长期目标。

DESCRIPTION (provided by applicant): 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/b-catenin pathway activation in pancreatic cancer cells play an important role in cell proliferation, invasion, and metastasis. Stability and nuclear translocation of b-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 b-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 b-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 b-catenin and promotes its nuclear translocation; Aim 2 will define the role of the interaction of b-catenin/FoxM1 in pancreatic tumor invasion and metastasis; and Aim 3 will to determine the expression of b-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 b-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 b-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 dysregulated Wnt/b-Catenin signaling and its crosstalk with FoxM1pathway. Translation of our findings into clinical patient care is another long-term goal of ours. PUBLIC HEALTH RELEVANCE: Crosstalk between b-catenin and FoxM1 signaling pathways and its impact on progressive growth and invasion of pancreatic cancer cells is unknown and our appealing evidence reveals a novel and significant research area of pancreatic cancer development and progression. Our studies integrate three levels of functional validating investigation: molecular biology, cell biology, and clinicohistopathology.