Dissecting PAF, an Accelerator of Colorectal Cancer

剖析 PAF——结直肠癌的加速剂

• 批准号: 9222715
• 负责人: Jae-Il Park
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-09 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222715
• 关键词: Ablation; Address; Binding; Binding Proteins; Biochemical; Biotechnology; Cell Proliferation; Cell physiology; Cells; ChIP-seq; Colorectal Cancer; Complement; Complex; Complication; DNA; DNA Methylation; DNA Repair; Development; Developmental Process; Epigenetic Process; Feedback; Future; Gene Expression Regulation; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Histone Deacetylase; Homeostasis; Human; Hypermethylation; Intervention; Intestines; Knock-out; Knockout Mice; Knowledge; Malignant Neoplasms; Mediating; Methods; Molecular; Mus; Mutation; Natural regeneration; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Pathologic; Pathway interactions; Protein Binding Domain; Proteomics; Public Health; Regulation; Research; Retinoblastoma; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Tissues; Tumorigenicity; Up-Regulation; WNT Signaling Pathway; adenoma; base; beta catenin; cancer cell; cancer genetics; cancer therapy; experimental study; frizzled related protein-1; gain of function; genome-wide analysis; in vivo; insight; interest; mouse model; novel strategies; prevent; promoter; public health relevance; success; therapeutic target; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): Fine control of Wnt signaling is essential for various cellular and developmental processes. However, deregulated Wnt signaling leads to colorectal cancer (CRC). Thus, elucidating the regulatory mechanisms of Wnt signaling to allow for its targeted manipulation is critical in CRC treatment. Our long-term goal is (i) to unravel distinct molecular mechanisms that promote intestinal tumorigenesis and (ii) to develop therapeutic methods to counter CRC cell proliferation and metastasis. Previous Studies - In addition to our consistent interest in Wnt signaling in cancer and development, we recently revealed that PCNA-associated factor (PAF) hyperactivates Wnt signaling and promotes CRC cell proliferation, strongly implies that PAF promotes intestinal tumorigenesis. Despite biologic functions of PAF in controlling DNA repair and Wnt signaling, pathologic roles of PAF in cancer are undetermined. Significance - With efforts by biotechnology groups have produced only limited success to date, there is a critical need to develop novel approaches to block the Wnt pathway. One complication is that Wnt signaling is indispensable to tissue homeostasis and regeneration. Thus, the targeting of Wnt signaling regulators whose expression is specifically restricted to cancer provides an opportunity to minimize normal tissue damage. Importantly, PAF expression is significantly elevated in CRC, but not in normal tissues. Additionally, PAF knockout (KO) mice are viable. These evidences indicate potential therapeutic advantages of specifically inhibiting Wnt signaling through manipulating PAF, a Wnt signaling regulator we identified. Thus, our proposed study is necessary to determine whether PAF is a therapeutic target for CRC. Based on our previous studies and preliminary results, we hypothesize that PAF accelerates intestinal tumorigenesis via Wnt signaling and epigenetic gene regulation. To test our hypothesis, we will accomplish the following specific aims: Aim 1 to determine in vivo tumorigenic role of PAF, using our genetically engineered mouse models; Aim 2 to dissect PAF-mediated silencing mechanism of Wnt antagonist in CRC; Aim 3 to determine the mechanism of PAF upregulation in CRC.

 描述（适用提供）：Wnt信号的精细控制对于各种蜂窝和发育过程至关重要。但是，放松管制的Wnt信号传导导致结直肠癌（CRC）。阐明Wnt信号传导的调节机制以允许其靶向操作，这对于CRC处理至关重要。我们的长期目标是（i）揭示促进肠道肿瘤发生的不同分子机制，以及（ii）开发治疗方法来对抗CRC细胞增殖和转移。先前的研究 - 除了我们对Wnt信号在癌症和发育中的持续兴趣外，我们最近透露，与PCNA相关的因子（PAF）过度激活WNT信号传导并促进CRC细胞增殖，这强烈暗示PAF促进肠道肿瘤发生。尽管PAF在控制DNA修复和WNT信号传导中的生物学功能，但PAF在癌症中的病理作用仍未确定。意义 - 迄今为止，生物技术组的努力仅产生有限的成功，因此需要开发新的方法来阻止Wnt途径。一种并发症是Wnt信号对于组织稳态和再生是必不可少的。这是Wnt信号调节剂的靶向，其表达特别局限于癌症提供了最大程度地减少正常组织损伤的机会。重要的是，在CRC中，PAF表达显着升高，但在正常组织中没有显着升高。此外，PAF敲除（KO）小鼠是可行的。这些证据表明，通过操纵PAF（我们确定的Wnt信号调节剂）特异性抑制Wnt信号传导的潜在治疗优势。这是我们提出的研究对于确定PAF是否是CRC的治疗靶点是必要的。基于我们以前的研究和初步结果，我们假设PAF通过Wnt信号传导和表观遗传基因调节加速了肠道肿瘤的发生。为了检验我们的假设，我们将使用我们的基因工程小鼠模型来实现以下特定目的：目标1确定PAF的体内肿瘤作用； AIM 2剖析CRC中Wnt拮抗剂的PAF介导的沉默机制；目标3确定CRC中PAF上调的机理。