Function and Regulation Mechanisms of Polo-like Kinase 3 in Pancreatic Cancer

项目摘要 胰腺癌是癌症研究中最大的挑战之一。胰腺 腺癌是美国成人癌症死亡的第四大原因。这个 五年存活率保持在1-3%，确诊后的中位生存期较短 比六个月还多。胰腺癌以局部晚期或转移性疾病为特征。 对目前的治疗缺乏反应。根据最频繁检测到的突变 这种疾病，一种胰腺癌的基因图谱正在出现。类马球的表现 蛋白激酶3(Plk3)是四种哺乳动物Polo样蛋白中的一种，在近 70%的人胰腺癌组织和大多数胰腺癌细胞系。此外， Plk3定位于染色体1p32，该基因被认为含有癌症易感基因。 最近，Plk3基因敲除小鼠被产生，这些小鼠发生了不同程度的肿瘤 器官在高龄的时候。Plk3是一种多功能蛋白质，在细胞周期调控中发挥重要作用。 细胞凋亡的调控和对DNA损伤的反应。Plk3的表达诱导细胞凋亡 脂质体对胰腺癌细胞的生长抑制作用 在异种移植小鼠模型中介导的基因转移。这些发现表明Plk3 作为一种肿瘤抑制因子，在胰腺癌细胞的凋亡中起着至关重要的作用。 然而，Plk3被调控的潜在分子机制仍然不清楚。 我们研究的长期目标是开发更有效的治疗方法 胰腺癌。根据我们的初步结果，我们假设Plk3的丢失 Plk3在胰腺癌的发生发展中起重要作用 激活是整合控制基因组不稳定性的信号的基本调节 通过可诱导的磷酸化和/或与接头分子的相互作用。测试我们的 假设，提出了三个具体的目的：(1)证明Plk3在 胰腺癌的发生；(2)确定Plk3在胰腺中的表达是否沉默 肿瘤与Plk3在控制细胞分裂和DNA损伤检查点的作用；(3)鉴定 Plk3激活的调控机制。我们建议的研究结果 将深入了解Plk3的调节机制以及Plk3作为一种 胰腺癌中的肿瘤抑制因子。重要的是，这项研究可能会发现新的分子 可能导致胰腺癌更有效治疗的目标。

Project Summary Pancreatic cancer poses one of the greatest challenges in cancer research. Pancreatic adenocarcinoma is the fourth-leading cause of adult cancer mortality in the United States. The five-year survival rate remains at 1-3%, and the median survival duration after diagnosis is less than six months. Pancreatic cancer is characterized by locally advanced or metastatic disease and lack of response to current therapies. Based on the most frequently detected mutations in this disease, a genetic profile for pancreatic cancer is emerging. The expression of polo-like kinase 3 (Plk3), one of the four mammalian polo-like kinases, is significantly decreased in nearly 70% of human pancreatic cancer tissues and in most pancreatic cancer cell lines. Furthermore, Plk3 localizes to chromosome 1p32, a locus thought to contain cancer susceptibility genes. Recently, Plk3-knockout mice were generated and these mice developed tumors in various organs at advanced age. Plk3 is a multi-functional protein that plays critical roles in the regulation of apoptosis and responses to DNA damage. Expression of Plk3 induced apoptosis in pancreatic cancer cells in cell culture and inhibited pancreatic tumor growth by liposome- mediated gene transfer in a xenograft mouse model. These findings demonstrate that Plk3 functions as a tumor suppressor and plays an essential role in pancreatic cancer cell apoptosis. However, the underlying molecular mechanism through which Plk3 is regulated remains elusive. The long-term goal of our research is to develop more effective therapies for patients with pancreatic cancer. On the basis of our preliminary results, we hypothesize that loss of Plk3 expression plays an essential role in the development of pancreatic cancer and that Plk3 activation is an essential regulation that integrates signals that control genomic instability through inducible phosphorylation and/or interaction with adaptor molecules. To test our hypotheses, three specific aims were proposed: (1) demonstrate the role of Plk3 in the development of pancreatic cancer; (2) determine the expression of Plk3 is silenced in pancreatic cancer and role of Plk3 in the control of cell division and DNA damage checkpoints; (3) identify the mechanisms by which activation of Plk3 is regulated. The findings from our proposed study will provide insight into the mechanisms of Plk3 regulation and the essential role of Plk3 as a tumor suppressor in pancreatic cancer. Importantly, this study may discover novel molecular targets that could lead to more effective treatments for pancreatic cancer.