NF-kB、YY1和miR-146a在去势抵抗性前列腺癌中相互调控的分子机制

The morbidity and the mortality of prostate cancer in China have been increasing every year as a result of the aging of the population. Castration refractory prostate cancer (CRPC) is very difficult to treat in clinic and also is a hot topic in basic studies. In our previous study, we found that the expression of miR-146a decreased during the progression of prostate cancer and over-expression of miR-146a in CRPC cell lines inhibited cells proliferation, migration and tumor formation in nude mice. However, the regulation of miR-146a expression remains largely unknown. Based on the results of bioinformatics analyses and preliminary experiments, we suppose that NF-kB-YY1-miR-146a regulatory circuitry contributes to CRPC. In present study, we want to prove that miR-146a is epigenetically silenced by YY1 and the polycomb group and NF-kB and YY1 are also repressed by over-expression of miR-146a. It will help to explain the down-regulation of miR-146a in CRPC and develop more effective drugs for CRPC patients.

随着我国人口老龄化，前列腺癌发病率与死亡率逐年升高。晚期去势抵抗性前列腺癌（CRPC）的治疗是临床治疗的难点也是目前研究的热点。在前期研究中，我们发现随着前列腺癌进展，miR-146a表达下降，且miR-146a抑制CRPC细胞增殖、迁移和裸鼠成瘤。而miR-146a在CRPC中转录调控机制仍不清楚。在生物信息学预测和预实验基础上，我们推测NF-kB、YY1和miR-146a相互调控参与CRPC发生发展。本研究拟从三者在临床标本中表达相关性出发，通过报告基因、EMSA、ChIP等实验验证①YY1与miR-146a启动子区结合，通过与Ezh2、H3K27、HDAC1形成复合体在表观遗传水平诱导miR-146a基因沉默；②miR-146a通过转录后调控抑制NF-kB通路活性和YY1的表达及功能。本研究对miR-146a转录调控机制的阐释具有重要意义，并为CRPC有效治疗药物开发提供理论依据。

随着我国人口老龄化，前列腺癌发病率与死亡率逐年升高。晚期去势抵抗性前列腺癌（CRPC）的治疗是临床治疗的难点也是目前研究的热点。在本项目中，我们对激素非依赖前列腺癌中NF-kB、YY1和miR-146a相互调控的机制进行了深入研究，得出以下结果，miR-146a在前列腺癌中表达降低，其表达与TNM分期及Gleason评分负相关，且与前列腺癌患者的预后有关；YY1与miR-146a在前列腺癌中表达呈负相关；高表达miR-146a和敲低YY1的表达能够促进前列腺癌细胞的凋亡，抑制前列腺癌的增殖、阻滞细胞周期、转移和以及移植瘤的生长；高表达YY1或EZH2能够抑制miR-146a的表达，敲低YY1或EZH2能够促进miR-146a的表达；YY1可以结合pri-miR-146a启动子区，招募EZH2，抑制miR-146a的转录；YY1和NF-KB通路为miR-146a的靶基因，受到miR-146a的调控。本项目系统的揭示NF-KB、YY1和miR-146a在去势抵抗性前列腺癌发生发展中相互调控的分子机制，为治疗去势抵抗性前列腺癌的有效药物开发提供理论依据。