lncRNA-p21/EZH2通路促进前列腺癌神经内分泌化的机制研究

Neuroendocrine prostate cancer (NEPC) is the most malignant type of prostate cancer. Since the androgen receptor (AR) is negative in NEPC, the current anti-androgen treatments don’t have any effects to reduce the NEPC growth. More importantly,several anti-androgen treatments can induce the prostate cancer neuroendocrine differentiation (NED), which could finally result in the resistance to the treatments and promote the cancer progression. Our preliminary results showed that lncRNA-p21 expression is increased in NEPC cells, and manipulation of lncRNA-p21 level can regulate the NED. The further investigation revealed that such regulation is dependent on the switch of the EZH2 methyltransferase activity.The long non-coding RNAs (lncRNAs) is the current hotspot of the cancer study. However, the lncRNA’s effects on prostate cancer NED are still not clear. In this study,we first propose to use the clinical samples to identify the correlation between the lncRNA-p21 level and expression of NE markers. And then we will investigate the mechanism how lncRNA-p21-EZH2 signal pathway promotes the NED via in vitro cell line study and in vivo mice model. Finally, we will test whether targeting lncRNA-p21-EZH2 signal can inhibit the NED via in vivo mice model. Our goal is to figure out the role of lncRNA-p21-EZH2 pathway in the process of NED, and find out the better way to inhibit the NEPC.

神经内分泌化前列腺癌（NEPC）是恶性程度最高的前列腺肿瘤。传统抗雄药物治疗效果不佳。多种抗雄药物能够显著诱导前列腺癌神经内分泌转化，进而产生耐药现象导致患者病情进展，但具体机制尚不明。文献报道多种长链非编码RNA（lncRNA）调控前列腺癌进展，我们推测前列腺癌神经内分泌化受lncRNA调节。前期研究发现神经内分泌化前列腺癌细胞中lncRNA-p21表达特异性升高，改变其功能表达后能显著改变细胞神经内分泌化水平，且该调节过程与其下游EZH2甲基转移酶功能转换有关。本研究拟通过临床标本明确lncRNA-p21-EZH2与NEPC标志物表达的相关性，进而利用细胞生物学及小鼠体外模型探讨lncRNA-p21-EZH2促进NEPC细胞分化的分子机理;最终通过小鼠体外模型研究以lncRNA-p21-EZH2为治疗靶点抑制或逆转NEPC分化可能性，进而延缓、治疗NEPC。

神经内分泌化前列腺癌（NEPC）是恶性程度最高的前列腺肿瘤。由于其缺少雄激素受体（AR）等常规治疗靶点，传统抗雄药物治疗效果不佳。多种抗雄药物能够显著诱导前列腺癌神经内分泌转化，进而产生耐药现象导致患者病情进展。我们研究发现神经内分泌化前列腺癌细胞中lncRNA-p21表达特异性升高，通过分子生物学实验证实AR可以与PCa细胞中lncRNA-p21启动子的结合，导致经恩杂鲁胺处理后的前列腺癌细胞中lncRNA-p21表达水平明显上调，高表达的lncRNA-p21与EZH2特异性结合并破坏PRC2复合物（EZH2、SUZ12和EED）。同时，lncRNA-p21进一步调控EZH2的磷酸化，并通过EZH2增强STAT3甲基化，从而促进前列腺癌神经内分泌化（NED）。本研究明确AR/lncRNA-p21/EZH2/STAT3通路与NEPC标志物表达的相关性，解释了恩杂鲁胺促进前列腺癌神经内分泌化的原因，并发现可以通过阻断AR/lncRNA-p21/ EZH2/STAT3通路来抑制恩杂鲁胺导致的前列腺癌神经内分泌化。