HMGB1在去势抵抗性前列腺癌AR信号通路再活化中的作用及机制研究

Reactivation of androgen receptor (AR) signaling pathway is the most important mechanism for the development and progression of castration-resistant prostate cancer (CRPC). Shockingly, the reactivation of AR signaling pathway in drug-resistant CRPC is not dependent of androgen regulation. Because the dimerization of AR is the critical step for AR signaling pathway reactivation, therefore, blocking the AR dimerization is an effective means of treating CRPC. High mobility group protein B1 (HMGB1) makes a considerable impact on transcription factor signaling pathway activation. Surprisingly, high expression level of HMGB1 is associated with poor prognosis of CRPC. Our data indicated that the expression level of HMGB1 was positive correlated with Gleason scores of prostate cancer (PC). Overexpression of HMGB1 promoted androgen independent growth of LNCaP cells and facilitated AR nuclear translocation under androgen deprivation condition. Base on the evidences listed above, we proposed a hypothesis that HMGB1 could be able to promoting the development and progression of CRPC by reactivating AR signaling pathway via regulating AR dimerization. In this study, we design to alter the expression level of HMGB1 (overexpress or knock down) of in vitro and in vivo models of prostate cancer in order to detecting impact of HMGB1 on AR dimerization and AR transcriptional activity, defining the role of HMGB1 in promoting the development and progression of CRPC, clarifying the molecular mechanism of HMGB1 in reactivating androgen independent AR signaling pathway. By completing this research, we will provide new targets and strategies for the prevention and treatment of CRPC.

雄激素受体（AR）信号通路再活化是去势抵抗性前列腺癌（CRPC）发生发展的重要机制，耐药性CRPC中AR信号通路不依赖于细胞内、外来源的雄激素而发生再活化，AR二聚化是再活化的关键步骤，因此阻断其二聚化是治疗CRPC的有效手段。高迁移率族蛋白B1（HMGB1）可促进转录因子信号通路活化，其表达水平与CRPC的预后有关。我们发现HMGB1表达水平与前列腺癌Gleason分级呈正相关，上调HMGB1表达可促进LNCaP细胞雄激素非依赖性生长，并促使AR以雄激素非依赖方式向细胞核转移。进而推测HMGB1可能通过调控AR二聚化，启动AR信号通路再活化，促进CRPC的发生发展。本研究拟利用体内外前列腺癌实验模型，通过上调或下调HMGB1的表达，检测AR的二聚化及转录活性，明确HMGB1在CRPC发生发展中的作用，阐明HMGB1启动AR信号通路再活化的分子机制，为防治CRPC提供新的靶点和思路。