PLCε/AR信号轴调控去势抵抗性前列腺癌发生发展的机制研究

The treatment of castration-resistant prostate cancer (CRPC) has been a universal conundrum for years, mainly because of the unclear mechanism underlying the pathogenesis of CRPC. The current point of view is that the persistent activation of androgen receptor (AR) signaling secondary to the up-regulation of AR in CRPC could be one of the most important triggering factors and supporting elements. However, the specific mechanisms responsible for this phenotype are not yet clear. We previously found that the expression of phospholipase Cε (PLCε) was positively associated with that of AR in prostate cancer, and that PLCε silencing was able to induce a remarkable autophagy-dependant degradation of AR. Moreover, we observed that the expressions of PLCε and AR increased synchronously during the modeling of CRPC in vitro. Therefore, we hypothesize that PLCε-mediated AR up-regulation and subsequent activation of AR signaling are pivotal pathogenetic mechanisms of CRPC. This study is to explore the detailed mechanisms of the PLCε-driven autophagy-dependant regulation of AR protein and its downstream signaling pathways, to clarify the role of PLCε/AR axis in the initiation and progression of CRPC, and to further comfirm the relationship between PLCε and AR via researches in tissue samples of prostate cancer (CRPC included). This study will focus on elaborating the specific mechanisms of CPRC pathogenesis in hope of discovering new molecular targets for therapeutic strategies.

去势抵抗性前列腺癌（CRPC）的治疗是一世界性难题，原因在于其发生机制现不完全明确。目前认为雄激素受体（AR）表达上调所致的AR通路持续激活是CRPC发生发展的最重要原因，但导致该表型的具体分子机制却了解甚少。我们前期发现，磷脂酶Cε（PLCε）在前列腺癌中与AR表达呈正相关，而沉默PLCε后能引起显著的自噬依耐性AR降解。此外，在CRPC细胞建模过程中我们发现，PLCε和AR表达同步出现明显上调。故我们推测，PLCε介导的AR高表达和AR通路激活可能是CRPC发生发展的重要分子机制之一。本课题拟通过建立多株CRPC细胞模型，探讨PLCε通过自噬依耐途径调节AR表达和AR信号通路的详细分子机制，明确PLCε/AR信号轴在CRPC发生发展的作用，并从临床前列腺癌（包括CRPC）组织标本中进一步佐证PLCε与AR的关系。通过上述研究以期探索CRPC的发生发展机制，为临床治疗提供潜在靶点。

去势抵抗性前列腺癌（CRPC）的治疗是一世界性难题，原因在于其发生机制现不完全明确。目前认为雄激素受体（AR）表达上调所致的AR通路持续激活是CRPC发生发展的最重要原因，但导致该表型的具体分子机制却了解甚少。本研究主通过建立多株CRPC细胞模型，探讨PLCε通过自噬依耐途径调节AR表达和AR信号通路的详细分子机制，明确PLCε/AR信号轴在CRPC发生发展的作用。我们发现前列腺癌中PLCε、AR蛋白及AR通路激活明显高于良性前列腺增生组织（其中CRPC组织最高），且随着前列腺肿瘤细胞的药物抵抗，PLCε和AR的蛋白表达均明显上升。PLCε/AR轴能够调控包括前列腺癌和CRPC细胞增殖、迁移、侵袭在内的多种生物学功能。PLCε能够调控细胞的选择性自噬，抑制AR蛋白降解，从而保证AR蛋白表达在较高水平，从而维持AR信号通路在前列腺癌细胞中的过度激活状态。此外，我们在后续探索中发现CPRC中高表达的PLCε能够抑制NIX蛋白的表达从而抑制线粒体自噬，我们推测上述作用导致受AR介导MtDNA异常转录增加，AR通路核外激活效应增加，CRPC中AR信号通路增强我们课题在研过程中，同时探索了RB1/TP53通路失活对前列腺癌的影响，结果显示在前列腺癌细胞中，RB1的下调可以通过TP53通路增强射线对DNA的破坏作用，PARP1抑制剂的联合使用可以明显增强前列腺癌细胞的射线治疗敏感性。我们的以上研究均旨在明确前列腺癌的发生发展机制，特别是从初步的药物抵抗到最终CPRC形成，研究中的通路及靶点为新兴药物的研制提供了理论基础。