The role of PLK1 in prostate cancer

 描述(申请人提供)：哺乳动物Polo-like kinase1(PLK1)是一种在细胞分裂的多个方面起关键作用的主要激酶，与人类癌症的发展密切相关，经常在包括前列腺癌(PCa)在内的各种癌症中过度表达。PLK1被认为是一种原癌基因；然而，由于缺乏合适的动物模型，目前仍缺乏支持这一观点的直接证据。这项拨款提案的总体目标是描绘PLK1过表达在前列腺癌发生和转移中的致癌作用。正在测试的假设是PLK1在前列腺癌的启动、进展和转移扩散过程中作为原癌基因发挥作用。我们的两个具体目标是：1)利用我们最近建立的前列腺特异性Plk1转基因小鼠模型，确定PLK1过表达在前列腺癌发生中的作用；2)通过阐明PLK1诱导的上皮-间充质转化和PCa细胞侵袭的分子机制，以及利用异种移植的PCa模型和Plk1转基因小鼠模型，确定PLK1过表达在PCa扩散中的作用。这项工作的发现将提供第一个体内证据，证明PLK1在前列腺癌中作为原癌基因发挥作用。此外，这些结果有望揭示PLK1的一种超越其典型作用的新功能，并确定PLK1在PCa的启动、进展和转移扩散中的致癌作用。从这项拟议的研究中获得的知识将从根本上促进我们对PLK1的致癌功能以及PCa发生和转移的分子基础的理解，这将有可能促进针对PLK1信号的治疗方案的优化，以显著提高抗癌疗效。此外，这一建议背后的想法可能适用于许多其他癌症，因为初步临床证据表明，PLK1参与了其他几种人类癌症的发生。

 DESCRIPTION (provided by applicant): Mammalian polo-like kinase 1 (PLK1), a major kinase with pivotal roles in multiple aspects of cell division, is closely associated with human cancer development and is frequently overexpressed in various cancers, including prostate cancer (PCa). PLK1 has been postulated to be a proto-oncogene; however, direct evidence to support this notion is still lacking, in part, due to the lack of appropriate animal models. The overall gol of this grant proposal is to delineate the oncogenic roles of PLK1 overexpression in PCa development and metastasis. The hypothesis being tested is that PLK1 functions as a proto-oncogene during PCa initiation, progression, and metastatic dissemination. Our 2 specific aims are: 1) to define the role of PLK1 overexpression in PCa development using our recently established prostate-specific Plk1 transgenic mouse model; and 2) to determine the role of PLK1 overexpression in PCa dissemination by elucidating the molecular mechanisms underlying PLK1-induced epithelial-mesenchymal transition and PCa-cell invasion and defining the pro-metastatic properties of PLK1 using xenograft PCa models and the Plk1 transgenic mouse model. The findings of this work will provide the first in vivo evidence that PLK1 functions as a proto-oncogene in PCa. Furthermore, the results are anticipated to uncover a novel function of PLK1 that goes beyond its canonical role, and to define the oncogenic roles of PLK1 during PCa initiation, progression, and metastatic dissemination. The knowledge gained from this proposed study will fundamentally advance our understanding of the oncogenic functions of PLK1 and the molecular basis of PCa development and metastatic dissemination, which have the potential to facilitate optimization of treatment regimens targeting PLK1 signaling to significantly enhance anticancer efficacy. Furthermore, the ideas behind this proposal may be generalizable to many other cancers since preliminary clinical evidence suggests that PLK1 is involved in the development of several other human cancers.