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

描述（由申请人提供）：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。5年生存率维持在1-3%，诊断后的中位生存期不到6个月。胰腺癌的特点是局部晚期或转移性疾病，对目前的治疗缺乏反应。基于这种疾病中最常检测到的突变，胰腺癌的基因谱正在出现。四种哺乳动物马球样激酶之一的马球样激酶3 （polo-like kinase 3, Plk3）在近70%的人胰腺癌组织和大多数胰腺癌细胞系中表达显著降低。此外，Plk3定位于染色体1p32，一个被认为包含癌症易感基因的位点。最近，plk3敲除小鼠被生成，这些小鼠在老年时在各个器官中出现肿瘤。Plk3是一种多功能蛋白，在细胞凋亡调控和DNA损伤应答中发挥关键作用。在细胞培养中表达Plk3诱导胰腺癌细胞凋亡，并通过脂质体介导的基因转移在异种移植小鼠模型中抑制胰腺肿瘤生长。这些发现表明Plk3作为肿瘤抑制因子在胰腺癌细胞凋亡中起重要作用。然而，调控Plk3的潜在分子机制仍然难以捉摸。我们研究的长期目标是为胰腺癌患者开发更有效的治疗方法。基于我们的初步结果，我们假设Plk3表达的缺失在胰腺癌的发展中起着至关重要的作用，并且Plk3激活是通过诱导磷酸化和/或与接头分子相互作用整合控制基因组不稳定性的信号的重要调控。为了验证我们的假设，我们提出了三个具体目标：(1)证明Plk3在胰腺癌发展中的作用；(2)确定Plk3在胰腺癌中的沉默表达以及Plk3在控制细胞分裂和DNA损伤检查点中的作用；(3)确定调控Plk3激活的机制。我们提出的研究结果将深入了解Plk3调控的机制以及Plk3作为肿瘤抑制因子在胰腺癌中的重要作用。重要的是，这项研究可能会发现新的分子靶点，从而导致更有效的胰腺癌治疗。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project is aimed at elucidating the tumor suppressor function of Plk3 in pancreatic tumor development and determining the novel mechanism by which Plk3 is silenced and regulated. We hypothesize that down regulation of Plk3 plays an essential role in development of pancreatic cancer and activation of Plk3 by proteolytic cleavage is regulated by PI3K. We will test our hypothesis by three specific aims using a combination of Plk3 knockout mouse models and Plk3 knockdown cell lines with biochemical and cell biological approaches, to fill in the gaps in our understanding of the novel molecular mechanisms of Plk3 regulation and role of Plk3 in tumorigenesis of pancreas.