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Wnt/?-catenin Signaling in Pancreatic Oncogenesis

胰腺肿瘤发生中的 Wnt/β-catenin 信号转导

基本信息

批准号：
10171806
负责人：
ANIRBAN MAITRA
金额：
$ 36.6万
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：
2017
资助国家：
美国
起止时间：
2017-09-14 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171806
关键词：
Affect Architecture Automobile Driving Behavior Biological CCND1 gene Cancer Biology Cell Proliferation Chromatin Chromatin Remodeling Factor Clinical Complex Consequentialism Cyclin D1 Disease Epigenetic Process FOXM1 gene Gelatinase A Gene Activation Gene Expression Genes Genetic Genetic Transcription Goals Histone H3 Human Intervention Link Lysine Malignant Neoplasms Malignant neoplasm of pancreas Mediating Modality Molecular Molecular Target Nature Pancreatic Intraepithelial Neoplasia Pattern Phenotype Play Preventive Proteins Regulation Research Role Signal Pathway Signal Transduction Site Specimen TCF7L2 gene Testing Therapeutic Time Transactivation Transcriptional Activation Tumorigenicity Up-Regulation WNT Signaling Pathway beta catenin c-myc Genes cancer cell cancer invasiveness cell growth clinically relevant clinically significant demethylation design effective intervention epigenetic regulation histone demethylase malignant phenotype novel overexpression pancreatic cancer cells pancreatic tumorigenesis premalignant promoter recruit self-renewal stem cells tumor tumor progression

项目摘要

Project Summary Progressive pancreatic cancer (PDA) is a lethal disease. The highly invasive and metastatic nature of PDA cells renders the tumor incurable. The molecular changes leading to this invasive behavior remain poorly understood. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our long-term research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategies to detect and treat PDA. The studies outlined in this proposal will directly determine the role of epigenetics in PDA progression by dissecting the functions of KDM4C, a histone demethylase, thus uncovering the causative mechanisms underlying the acquisition of PDA invasive phenotype, a hallmark of PDA progression. It is well established that Wnt/β-catenin signaling is critical for cancer cell proliferation, invasion and cancer progression, whereas little is known about the epigenetic mechanisms for the activation of those tumor-promoting genes downstream of Wnt/β-catenin signaling. We found for the first time that KDM4C is drastically increased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially elevated KDM4C expression. Concurrently, our recent study also has shown a consistent increased expression of genes downstream of Wnt/β-catenin signaling in invasive PDA as compared to that in PanINs. Causally linking KDM4C to overactivation of Wnt/β-catenin signaling and functionally interrogating the underlying mechanisms are fundamentally important in understanding PDA progression and designing effective intervention strategies. We postulate that upregulation of KDM4C expression and function causes overactivation of Wnt/β-catenin signaling and consequential acquisition of malignant phenotype in PDA, i.e., a switch from premalignant PanINs to invasive PDA. To test our hypothesis, we propose three specific aims: 1) to investigate the role and mechanisms of KDM4C in enhancing Wnt/β-catenin transcriptional function and uncover a novel mechanism for the persistent activation of β-catenin-mediated transcription in PDA (Aim 1); 2) to evaluate the function of KDM4C expression on PDA biology (Aim 2); and 3) to investigate the molecular mechanisms underlying the dysregulated KDM4C expression and its clinical relevance and significance in PDA progression (Aim 3). If the studies of those specific aims are completed, not only will we uncover new molecular mechanisms for the activation of Wnt/β-catenin signaling pathways during PDA progression, but also for first time will we reveal the biological and clinical impacts of the epigenetic regulation in general and KDM4C in particular on PDA progression; and help identify potential targets for developing novel intervention strategies.

项目总结