Wnt/?-catenin Signaling in Pancreatic Oncogenesis

胰腺肿瘤发生中的 Wnt/β-catenin 信号转导

• 批准号: 9565530
• 负责人: ANIRBAN MAITRA
• 金额: --
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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/9565530
• 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; Premalignant; Preventive; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; Specimen; Stem cells; 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; promoter; recruit; self-renewal; tumor; tumor progression

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.

项目概要 进行性胰腺癌（PDA）是一种致命的疾病。其高度侵袭性和转移性 PDA 细胞使肿瘤无法治愈。导致这种侵入行为的分子变化仍然很差 明白了。虽然某些遗传和表观遗传改变多年来已为人所知，但迄今为止，这一点已经被人们所熟知。 没有产生有用的预防和/或治疗方式。我们的长期研究目标是确定 驱动基因表达的改变，可用于制定有效的检测和治疗策略 掌上电脑。本提案中概述的研究将通过以下方式直接确定表观遗传学在 PDA 进展中的作用： 剖析 KDM4C（一种组蛋白去甲基化酶）的功能，从而揭示其致病机制 PDA 侵袭性表型的获得是 PDA 进展的标志。 众所周知，Wnt/β-连环蛋白信号传导对于癌细胞增殖、侵袭和转移至关重要。 癌症进展，而对于激活这些癌症的表观遗传机制知之甚少 Wnt/β-连环蛋白信号下游的促肿瘤基因。我们第一次发现KDM4C是 侵入性 PDA 急剧增加，这种失调严重促进 PDA 生物学，而 PanINs 不表现出显着升高的 KDM4C 表达。同时，我们最近的研究也表明 侵入性 PDA 中 Wnt/β-catenin 信号下游基因的表达持续增加 与 PanIN 中的相比。 KDM4C 与 Wnt/β-catenin 信号传导过度激活之间的因果关系 从功能上探究潜在机制对于理解 PDA 至关重要 进展并设计有效的干预策略。 我们假设 KDM4C 表达和功能的上调导致 Wnt/β-catenin 过度激活 PDA 中恶性表型的信号传导和随之而来的获得，即从癌前状态的转变 PanIN 到侵入式 PDA。为了检验我们的假设，我们提出了三个具体目标：1）调查角色和 KDM4C增强Wnt/β-catenin转录功能的机制并揭示新机制 用于 PDA 中 β-连环蛋白介导的转录的持续激活（目标 1）； 2）评估功能 KDM4C 在 PDA 生物学上的表达（目标 2）； 3）研究其背后的分子机制 KDM4C 表达失调及其在 PDA 进展中的临床相关性和意义（目标 3）。 如果这些特定目标的研究完成，我们不仅会发现新的分子机制 在 PDA 进展过程中激活 Wnt/β-catenin 信号通路，也是我们第一次 揭示表观遗传调控的生物学和临床影响，特别是 KDM4C PDA进展；并帮助确定制定新干预策略的潜在目标。