Functional Validation of Pancreatic Cancer Progression Biomarker

胰腺癌进展生物标志物的功能验证

• 批准号: 8094403
• 负责人: KEPING XIE
• 金额: $ 31.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8094403
• 关键词: Address; Area; Biological Markers; Cancer Biology; Cancer Cell Growth; Cell Proliferation; Cellular biology; Clinical; Data; Development; Disease; Epigenetic Process; Genetic; Goals; Growth; Human; Investigation; Lead; Malignant neoplasm of pancreas; Mediating; Modality; Molecular; Molecular Biology; Molecular Target; Neoplasm Metastasis; Nuclear Translocation; Pathogenesis; Pathway interactions; Patient Care; Play; Proteins; Research; Resources; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Translations; Tumor Cell Invasion; Tumorigenicity; Validation; base; cancer diagnosis; cancer therapy; clinically relevant; clinically significant; design; malignant phenotype; novel; pancreatic cancer cells; pancreatic neoplasm; public health relevance; research study; transcription factor; tumor progression

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.

描述（由申请人提供）：转移性胰腺癌是一种致命的疾病。胰腺癌发育和进展背后的遗传和表观遗传学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。最近的研究表明，胰腺癌细胞中异常的Wnt/B-catenin途径激活在细胞增殖，侵袭和转移中起重要作用。 B-catenin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。我们最近的研究还表明，转录因子FOXM1批判性地有助于人类胰腺癌的细胞增殖，侵袭和肿瘤性。重要的是，我们的研究表明，FOXM1和B-catenin在胰腺癌细胞中的身体和功能上似乎相互关联。 先前的研究（包括我们自己的）足以使我们相信FOXM1和B-catenin信号之间的相互作用在胰腺癌的发展和进展中起着至关重要的作用。为了检验我们的假设，我们设计了几组实验，这些实验围绕三个具有定义明确的目标的特定目标。 AIM 1将确定FOXM1是否与B-catenin相互作用并促进其核易位； AIM 2将定义B-catenin/foxm1相互作用在胰腺肿瘤侵袭和转移中的作用； AIM 3将确定B-catenin和FoxM1在胰腺癌组织中的表达，并描述它们在人胰腺癌发病机理中的临床意义。因此，我们的研究整合了三个级别的功能验证研究：分子生物学，细胞生物学和临床组织病理学。 我们提出的研究的完成将代表我们理解B-catenin和FoxM1表达和功能的深入机理的重大进步，尤其是胰腺癌的发展及其进展。因此，我们提出的研究对于了解B-catenin信号传导与FOXM1信号传导之间的相互作用及其功能对胰腺癌生物学的影响至关重要，并确定其作为设计有效方式以控制胰腺癌细胞生长，侵袭和转移的分子靶标。从长远来看，我们的研究还可以进一步研究介导失调的Wnt/B-catenin信号传导及其与FoxM1Pathway的串扰的分子机制。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。 公共卫生相关性：B-catenin和FoxM1信号通路之间的串扰及其对胰腺癌细胞的进行性生长和侵袭的影响尚不清楚，我们的有吸引力的证据揭示了胰腺癌发育和进展的新颖而重要的研究领域。我们的研究整合了三个级别的功能验证研究：分子生物学，细胞生物学和临床组织病理学。