中心体数目扩增是肿瘤细胞的特征之一。中心体扩增能够诱导染色体不稳定、破坏组织稳态、促进细胞的浸润与侵袭，具有促进肿瘤发生发展的能力。我们前期在转基因小鼠的研究发现中心体扩增能够促进小鼠前列腺上皮内瘤的生成。然而，中心体扩增影响前列腺肿瘤发生发展的机制尚不明确。本研究利用转基因小鼠，在体内特异性地诱导前列腺上皮中心体扩增，探讨其通过何种细胞与分子机制影响前列腺癌的发生与发展；并通过转基因，在体内随机诱导单个前列腺肿瘤细胞中心体扩增、追踪这些肿瘤细胞在去雄性激素治疗后肿瘤复发转移过程中的作用；继而通过cDNA芯片从转基因小鼠中筛选诱导前列腺上皮中心体扩增的重要分子、中心体扩增激活的肿瘤相关信号转导通路、以及这些通路上的关键分子；并在临床前列腺癌组织上验证这些分子对人前列腺癌发生发展的影响。本项目的完成可明确中心体扩增影响前列腺癌发生发展的作用及其机制并可为临床前列腺癌的诊断与治疗提供新的靶点。

Centrosome amplifications, the hallmarks of human cancer, can induce the chromosomal instability, disturb the integrity of tissue homeostasis and trigger cell invasions. Several in vitro and in vivo studies have shown that centrosome amplifications can promote the tumorigenesis and tumor progression. Clinical evidences also indicate that centrosome amplifications are correlated with the poor diagnosis and malignancy of human tumors. Previously, we have shown that centrosome amplifications can promote the formation of prostatic intraepithelial neoplasia (PIN) in a transgenic mouse model. However, it is still unknown whether and how centrosome amplifications affect the tumorigenesis and/or tumor progression of the prostate. In this project, we propose to study the molecular and cellular mechanisms underlying the centrosome amplification-elicited tumor formation through specifically inducing the centrosome amplifications in the mouse prostate epithelium. In addition, we will use a genetic strategy that randomly induces centrosome amplifications on individual tumor cells and trace these cells over time during the relapse and metastasis of castration-resistant prostate tumors. Furthermore, we will perform a high-throughput screening to identify molecules that could induce the centrosome amplification in the prostate epithelium and to identify the tumor-related signaling pathways elicited by the centrosome amplification as well as the critical molecule involved. Finally, we will determine the function of these molecules on human prostate tumorigenesis and tumor progression by using clinical prostate tumor tissues and cancer cell lines. These studies will facilitate us to understand whether and how centrosome amplifications affect the tumorigenesis and/or tumor progression of the prostate epithelium and identify molecules that could prevent or treat the human prostate cancer.