Wnt/?-catenin Signaling in Pancreatic Oncogenesis

项目摘要 进行性胰腺癌（PDA）是一种致命的疾病。高侵袭性和转移性 PDA细胞使肿瘤无法治愈。导致这种入侵行为的分子变化仍然很差 明白虽然某些遗传和表观遗传改变已经众所周知多年，但迄今为止， 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 驱动基因表达的改变，可用于开发有效的策略，以检测和治疗 掌上电脑。本提案中概述的研究将直接确定表观遗传学在PDA进展中的作用， 剖析组蛋白去甲基化酶KDM 4C的功能，从而揭示致病机制 作为获得PDA侵袭性表型的基础，这是PDA进展的标志。 已经确定Wnt/β-连环蛋白信号传导对于癌细胞增殖、侵袭和增殖是至关重要的。 癌症进展，而很少有人知道的表观遗传机制的激活， Wnt/β-catenin信号传导下游的肿瘤促进基因。我们首次发现KDM 4C是 在侵袭性PDA中急剧增加，这种失调严重促进PDA生物学，而PanIN 没有表现出显著升高的KDM 4C表达。同时，我们最近的研究也表明， 在侵袭性PDA中，Wnt/β-catenin信号下游基因的表达持续增加， 与PanIN相比。KDM 4C与Wnt/β-连环蛋白信号转导过度活化的因果关系 从功能上探究潜在的机制对于理解PDA至关重要 制定有效的干预策略。 我们推测KDM 4C表达和功能的上调导致Wnt/β-catenin过度活化， 信号传导和随后获得PDA中的恶性表型，即，从癌前病变 PanIN到侵入性PDA。为了验证我们的假设，我们提出了三个具体目标：1）调查的作用， KDM 4C增强Wnt/β-catenin转录功能的机制，并揭示了一种新的机制 目的1）研究β-catenin介导的转录在PDA中的持续激活; 2）评价 KDM 4C在PDA生物学上的表达（目的2）;和3）研究KDM 4C在PDA生物学上的表达的分子机制。 KDM 4C表达失调及其在PDA进展中的临床相关性和意义（目的3）。 如果这些特定目标的研究得以完成，我们不仅会发现新的分子机制， 在PDA进展过程中Wnt/β-catenin信号通路的激活，也是我们第一次将 揭示了表观遗传调控的生物学和临床影响，特别是KDM 4C， PDA进展;并帮助确定开发新的干预策略的潜在目标。

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.