Dissecting PAF, an Accelerator of Colorectal Cancer

 描述(由申请人提供)：Wnt信号的精细控制对于各种细胞和发育过程是必不可少的。然而，Wnt信号失控会导致结直肠癌。因此，阐明Wnt信号的调节机制以允许其靶向操作在结直肠癌的治疗中至关重要。我们的长期目标是(I)揭开促进肠道肿瘤发生的不同分子机制，(Ii)开发抗结直肠癌细胞增殖和转移的治疗方法。先前的研究-除了我们对Wnt信号在癌症和发育中的持续关注之外，我们最近发现，增殖细胞核抗原相关因子(PAF)过度激活Wnt信号并促进CRC细胞的增殖，强烈暗示PAF促进肠道肿瘤的发生。尽管PAF在控制DNA修复和Wnt信号方面具有生物学功能，但其在癌症中的病理作用尚不清楚。重大意义--由于生物技术团体的努力到目前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信号对于组织的动态平衡和再生是不可或缺的。因此，靶向表达仅限于癌症的Wnt信号调节因子提供了一个将正常组织损伤降至最低的机会。重要的是，PAF在结直肠癌中的表达显著升高，但在正常组织中不表达。此外，PAF基因敲除(KO)小鼠是存活的。这些证据表明，通过操纵PAF(我们确定的Wnt信号调节因子)来特异性地抑制Wnt信号转导具有潜在的治疗优势。因此，我们建议的研究对于确定PAF是否是CRC的治疗靶点是必要的。根据我们以前的研究和初步结果，我们假设PAF通过Wnt信号和表观遗传基因调控促进肠道肿瘤的发生。为了验证我们的假设，我们将完成以下特定目的：目的1利用我们的基因工程小鼠模型确定PAF在体内的致瘤作用；目的2剖析PAF介导的Wnt拮抗剂在结直肠癌中的沉默机制；目的3确定PAF在结直肠癌中上调的机制。

 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.