Dissecting PAF, an Accelerator of Colorectal Cancer

 描述（由申请人提供）：Wnt信号传导的精细控制对于各种细胞和发育过程至关重要。然而，失调的Wnt信号传导导致结直肠癌（CRC）。因此，阐明Wnt信号传导的调节机制以允许其靶向操纵在CRC治疗中至关重要。我们的长期目标是（i）解开促进肠道肿瘤发生的不同分子机制，（ii）开发治疗方法来对抗CRC细胞增殖和转移。以前的研究-除了我们对癌症和发展中的Wnt信号传导的一贯兴趣外，我们最近发现PCNA相关因子（PAF）过度激活Wnt信号传导并促进CRC细胞增殖，强烈暗示PAF促进肠道肿瘤发生。尽管PAF在控制DNA修复和Wnt信号传导中具有生物学功能，但PAF在癌症中的病理作用尚未确定。意义-生物技术小组的努力迄今为止只取得了有限的成功，迫切需要开发新的方法来阻断Wnt途径。一个复杂的问题是，Wnt信号是组织稳态和再生不可或缺的。因此，其表达特异性限于癌症的Wnt信号传导调节剂的靶向提供了使正常组织损伤最小化的机会。重要的是，PAF表达在CRC中显著升高，但在正常组织中不显著。此外，PAF敲除（KO）小鼠是存活的。这些证据表明，通过操纵PAF特异性抑制Wnt信号传导具有潜在的治疗优势，PAF是我们鉴定的Wnt信号传导调节剂。因此，我们提出的研究是必要的，以确定是否PAF是CRC的治疗靶点。基于我们以前的研究和初步结果，我们推测PAF通过Wnt信号和表观遗传基因调控加速肠道肿瘤的发生。为了验证我们的假设，我们将完成以下具体目标：目的1，确定PAF在体内致瘤作用，使用我们的基因工程小鼠模型;目的2，剖析PAF介导的Wnt拮抗剂在CRC中的沉默机制;目的3，确定PAF在CRC中上调的机制。

 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.