Functional Validation of Pancreatic Cancer Progression Biomarker

胰腺癌进展生物标志物的功能验证

基本信息

批准号：
8517602
负责人：
KEPING XIE
金额：
$ 29.89万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-07-31
项目状态：
已结题

项目摘要

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.

项目摘要/总结转移性胰腺癌是一种致命的疾病，其遗传和表观遗传改变。胰腺癌发生和进展背后的分子信号随之发生的变化目前尚不清楚，进展生物标志物的功能鉴定和验证至关重要。最近的研究表明胰腺癌的异常诊断和治疗。 Wnt/¿ -连环蛋白通路激活在胰腺癌细胞中发挥重要作用的增殖、侵袭和转移。 -连环蛋白是我们最近的研究也发现了导致胰腺癌恶性表型的关键步骤。表明转录因子 FoxM1 对细胞增殖、侵袭和重要的是，我们的研究表明 FoxM1 和 ¿ -连环蛋白在胰腺癌中似乎在物理和功能上相互关联细胞。包括我们自己在内的先前研究足以使我们相信相互作用 FoxM1 和 ¿ 之间- 连环蛋白信号在胰腺癌的发生和发展中发挥着关键作用为了验证我们的假设，我们设计了几组实验围绕三个明确目标的具体目标，目标 1 将决定 FoxM1 是否相互作用。和 -连环蛋白并促进其核易位；目标 2 将定义相互作用的作用； ¿ -catenin/FoxM1在胰腺肿瘤侵袭和转移中的作用和Aim 3将确定的表达 ¿ -胰腺癌组织中的连环蛋白和 FoxM1 及其临床描述在人类胰腺癌发病机制中的重要性因此，我们的研究整合了三个层面。功能验证研究：分子生物学、细胞生物学和临床组织病理学。完成我们提出的研究将代表我们的理解取得了实质性进展失调的深层机制 ¿ -catenin 和 FoxM1 的一般表达和功能特别是在胰腺癌的发展和进展中，我们提出的研究是。了解 ¿ 之间的相互作用至关重要-连环蛋白信号传导和 FoxM1 信号传导及其功能对胰腺癌生物学的影响，并确定其作为胰腺癌的价值设计有效控制胰腺癌细胞生长、侵袭方式的分子靶点从长远来看，我们的研究还可以导致对分子的进一步研究。调节 Wnt/¿ 失调的机制-连环蛋白信号传导及其与 FoxM1 通路的串扰。将我们的研究结果转化为临床患者护理是我们的另一个长期目标。