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。高度侵袭性和转移性 PDA细胞使肿瘤无法治愈。导致这种侵入性行为的分子变化仍然很差。 明白了。虽然某些基因和表观遗传变化多年来一直是众所周知的，但到目前为止 没有导致有效的预防和/或治疗方式。我们的长期研究目标是确定 驱动基因表达的变化，可用于开发有效的检测和治疗策略 掌上电脑。这项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 解析组蛋白去甲基酶KDM4C的功能，从而揭示其致病机制 获得PDA侵袭性表型的潜在原因是PDA进展的标志。 Wnt/β-连环蛋白信号转导通路在癌细胞增殖、侵袭和转移过程中起重要作用。 癌症进展，而对激活这些基因的表观遗传机制知之甚少 Wnt/β-连环蛋白信号转导下游的促肿瘤基因。我们首次发现KDM4C是 侵袭性PDA急剧增加，这种失调严重促进了PDA生物学，而Panins 不表现出显著升高的KDM4C表达。同时，我们最近的研究还表明， 侵袭性动脉粥样硬化患者Wnt/β-catenin信号转导下游基因表达持续增强 与帕宁斯相比。KDM4C与Wnt/β-catenin信号的过度激活和 从功能上询问潜在的机制对于理解PDA是至关重要的 并设计有效的干预策略。 我们推测KDM4C的表达和功能上调导致Wnt/β-连环蛋白的过度激活 PDA中恶性表型的信号转导和相应的获得，即从癌前状态转换 从Panins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 KDM4C增强Wnt/β-catenin转录功能的机制及新机制的揭示 持续激活β-连环蛋白介导的转录在动脉导管未闭中的作用(目标1)； KDM4C在PDA生物学上的表达(目标2)；以及3)研究在PDA生物学中的分子机制。 KDM4C异常表达及其在PDA进展中的临床意义(目标3)。 如果完成对这些特定目标的研究，我们不仅将发现新的分子机制 对于动脉导管未闭进展过程中Wnt/β-连环蛋白信号通路的激活，但也是我们第一次 揭示表观遗传调控的一般生物学和临床影响，特别是KDM4C对 PDA进展；并帮助确定开发新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.