hZimp7调控前列腺癌STAT3信号的作用机制研究

Prostate cancer is generated from the combined effects of androgen receptor (AR) signaling and bypass proliferation signaling, such as STAT3 pathway. It is critical to identify the regulatory protein of AR bypass signaling to reveal the pathogenesis of prostate cancer. We found that a bona fide AR transcriptional co-activator, hZimp7, is a novel STAT3-interacting protein that regulates phosphorylation and nuclear translocation of STAT3, and uniquely functions on STAT3 activation in the members the ZMIZ family. The purpose of this study is to provide more evidence for the existing work to reveal the function of hZimp7. ① To demonstrate the important role of hZimp7 in activating STAT3 signaling and to determine its structural basis of the signal activation. ② To clarify the hZimp7 expression levels associated with STAT3 activation, and associated with tumor development and prognosis in human prostate cancer tissue samples. ③ To identify the known and unknown downstream targets of hZimp7/STAT3 signal. ④ To investigate the relationship between hZimp7 in the regulation of STAT3 Sumoylation and in regulation of STAT3 phosphorylation. ⑤ To reveal the roles of hZimp7 synergistic STAT3 signal in the tumorigenesis of prostate cancer. The purpose of this project is to reveal the biological significance of hZimp7 in STAT3 signal regulation in prostate cancer, and further to provide the mechanisms of ihZimp7 as a possible novel oncogene in prostate cancer.

前列腺癌是雄激素受体(AR)信号和旁路STAT3等增殖信号共同作用的结果；揭示前列腺癌机理的核心问题是寻找AR旁路调控蛋白。我们发现一个真正意义上的AR转录共激活因子，hZimp7蛋白；并初步发现它在ZMIZ家族中具有独特的STAT3信号激活作用，调节STAT3磷酸化和入核过程，可能是一种新型STAT3激活蛋白。本研究旨在已有工作基础上，①证明hZimp7活化STAT3信号的重要作用，确定信号活化的结构基础；②明确hZimp7表达水平与人前列腺癌组织中STAT3活化和与肿瘤发展预后的关联性；③揭示hZimp7/STAT3信号已知和未知的下游靶点；④探讨hZimp7调节STAT3蛋白SUMO化修饰与磷酸化修饰之间的关系；⑤揭示hZimp7协同STAT3信号对前列腺癌发生的作用。本项目旨在阐明hZimp7调控前列腺癌STAT3信号的作用机制，提供其可能作为新型癌基因的生物学证据。

前列腺癌STAT3信号异常活化的机制还不清楚，本项目研究了hZimp7调控前列腺癌STAT3信号的作用机制。①证明hZimp7活化STAT3信号的重要作用，确定信号活化的结构基础。我们证明hZimp7作为转录共调节因子，与STAT3结合，并促进了STAT3信号的转录活性和STAT3介导的前列腺癌细胞生长。②明确hZimp7表达水平与人体前列腺癌肿瘤发展预后关联。我们证明，前列腺癌hZimp7高表达，且表达于癌组织的细胞核和细胞浆；通过组织芯片的免疫组化和临床前列腺癌的10年生存数据，证明前列腺癌hZimp7的表达增强，且与肿瘤恶性程度Gleason评分高度相关，hZimp7表达增高患者预后不良。③揭示hZimp7/STAT3信号已知和未知的下游靶点。我们证明hZimp7促进STAT3信号经典靶基因（增殖基因）的表达。特别是，发现hZimp7/STAT3共同调控三个特异基因，结合和开启DVL3、MLL4、CDK13基因启动子的STAT3E序列，促进基因转录和蛋白表达。选择DVL3作为代表，证明hZimp7/STAT3-DVL3信号调控STAT3经典信号的基因表达。④探讨hZimp7调节STAT3蛋白磷酸化修饰之间的关系。我们证明，hZimp7促进STAT3的磷酸化，并于p-STAT3具有相互作用。STAT3的磷酸化位点，705位酪氨酸参与hZimp7对STAT3细胞核转位、转录活性和细胞增殖的调节作用。⑤动物实验证明hZimp7调控前列腺增殖信号。证明hZimp7敲入杂合子（hZimp7kin）小鼠前列腺脏器指数上升，增殖指标Ki67增强，转录组学Ras信号基因活化；hZimp7kin小鼠促进了前列腺原位荷瘤细胞的生长。所以，本项目阐明了hZimp7调控前列腺癌STAT3信号的作用机制，提供了hZimp7作为新型癌基因的生物学证据。