去势抵抗性前列腺癌（CRPC）是前列腺癌治疗的难点。既往研究证实：前列腺癌干细胞在CRPC发生和转化过程中发挥重要作用，但其分子机制尚不明确。本课题前期研究结果提示：LRH-1在具有干性的前列腺癌细胞中高表达；干预LRH-1表达可影响前列腺癌干细胞的功能；同时，LRH-1可调控肿瘤干细胞关键因子OCT4的表达。我们推测：LRH-1可能通过诱导OCT4的表达参与前列腺癌干细胞干性的维持，进而促进CRPC的发生发展。本项目拟：（1）通过干预LRH-1的表达或活性进一步阐明LRH-1调控前列腺癌干细胞干性的功能；（2）验证LRH-1通过OCT4调控前列腺癌干细胞干性的机制；（3）通过干预CRPC移植瘤内或携瘤小鼠体内LRH-1的表达或活性，评估LRH-1作为CRPC治疗靶点的临床转化价值。本研究成果将首次阐明LRH-1维持前列腺癌干细胞干性的作用和机制，为CRPC治疗新靶标的开发提供科学依据。

Currently, Castration-resistant prostate cancer (CRPC) is an incurable disease and represents a major clinical hurdle. Although the exact mechanisms underlying the progression to hormone-independent stage are still incompletely understood, emerging evidence has shown that prostate cancer stem cells (CSCs) endowed with self-renewal capacity and differentiation potential (stemness) may be involved in prostate tumor initiation, recurrence and progression to castration-resistant stage. Our previous results showed LRH-1 exhibited up-regulated expression pattern in enriched prostate cancer stem cells and CRPC xenograft model. Functional studies revealed that LRH-1 could promote stem-like properties in prostate cancer cells, as its over-expression enhanced the self-renewal capacity and conferred resistance to anti-androgen drugs (bicalutamide), chemo-therapeutic agents (paclitaxel) and androgen deprivation condition (charcoal-stripped serum) in prostate cancer cells, whereas its knockdown or inactivation triggered self-renewal arrest in vitro and suppressed tumourigenicity in vivo. Moreover, we demonstrated that OCT4, a vital non-cell surface marker for CSCs, could be transactivated by LRH-1. Based on these intriguing results, we hypothesize that LRH-1 may play a tumour-promoting role in the malignant growth of prostate cancer through its maintenance of CSCs via its transactivation of the OCT4 gene. This proposal will achieve the following goals: (1) to determine the functional role of LRH-1 in regulating the stemness of prostate cancer stem cells by “loss-of-function” and “gain-of-function” study or GFP-tracking system, (2) to explore and identify the mechanism underlying the LRH-1-mediated maintenance of stemness in prostate cancer stem cells by bioinformatics analysis, luciferase reporter assay, ChIP assay and rescue experiments. (3) To assess the therapeutic significance and application of targeting LRH-1 in CRPC treatment via inhibition of LRH-1 activity in vivo by a LRH-1-specific inverse agonist or knockdown of LRH-1 expression in vivo by siRNA. We expect through this study, it could help to provide a better understanding on the mechanisms responsible for the enhanced stemness in CRPC progression and resistance to hormone- or chemo-therapy in CRPC patients, and also to appraise the potential value of LRH-1 as a novel therapeutic target in CRPC treatment.