核受体TLX在前列腺癌干细胞自我更新中的作用及机制研究

Castration-resistant (CRPC) progression is the main pathological characteristic of advanced prostate cancer. The putative prostate cancer stem cells are likely to form a resistant core after androgen-deprivation therapies, contributing to the development of castration-resistant disease. Our previous study demonstrates that orphan nuclear receptor TLX plays an oncogenic role in prostate cancer carcinogenesis and malignant progression via inhibition of Oncogene-induced cellular senescence. Further study showed that TLX shows overexpression pattern in enriched prostate cancer stem cells and castration-resistant prostate cancer model, and specific inhibition of TLX can significantly impair the tumorigenesis of prostate cancer stem cells. Based on these interesting results, we hypothesis that TLX is involved in growth and self-renewal regulation of prostate cancer stem cells which contribute to castration-resistance progression. This proposal will achieve the following goals: (1) to determine the functional role of TLX in prostate cancer stem cell growth and self-renewal by GFP-tracking system, (2) to identify the underlying regulation mechanism of TLX in prostate cancer stem cells by gene expression profiling and transcriptional network analysis, (3) to elucidate the functional role of cancer stem cell-regulating TLX in castration-resistant prostate cancer (CRPC) by CRPC mouse models, (4) to assess the potential therapeutic value of targeting to TLX in the treatment of prostate cancer by retroviral delivering siTLX. We propose to clarify the mechanism(s) that governing prostate cancer stem cells, providing scientific basis for establishment of therapeutic target for advanced prostate cancer.

去势抵抗性前列腺癌（CRPC）的发生机制尚不明确。最新研究发现：肿瘤干细胞存在于前列腺癌组织中，并对其发生发展起重要作用。前期研究结果证明核受体TLX能促进前列腺癌的恶性进展。并且，TLX在前列腺癌干细胞和CRPC中高表达；特异性抑制TLX后，能显著降低前列腺癌干细胞的成瘤能力。因此，我们推测：TLX可能通过调控前列腺癌干细胞的自我更新促进CRPC的发生。本项目拟：(1) 采用GFP谱系追踪方法证明TLX对前列腺癌干细胞自我更新的调控，(2)结合基因表达谱芯片和转录因子分析技术研究TLX的调控机制，(3) 通过CRPC异体移植瘤小鼠模型验证TLX促进CRPC的转化，(4) 采用腺相关病毒携带siTLX方法探讨TLX作为前列腺癌治疗靶点的潜在能力。本研究成果将首次阐明TLX促进前列腺癌干细胞自我更新的作用和机制，为晚期前列腺癌治疗新靶标提供更充分的科学依据。

去势抵抗性前列腺癌（CRPC）的发生机制尚不明确。研究发现，肿瘤干细胞的存在，是前列腺癌细胞转化为CRPC、逃脱放疗和化疗以及复发的重要原因。本团队一直致力于核受体TLX在前列腺癌发生发展中的功能性研究以及其作为前列腺癌治疗靶点的探索研究，本项目旨在探讨TLX在前列腺癌干细胞的自我更新中的调控促进CRPC的发生的功能与机制。本研究首先建立了前列腺癌干细胞富集培养、扩增体系，发明了一种的经济、高效的培养前列腺癌干细胞 的新方法；系统研究了TLX等孤儿核受体在前列腺癌干细胞和CRPC小鼠模型中的表达谱，表明了TLX在前列腺癌肿瘤干细胞和CRPC进展中的重要作用。然后，本项目深入研究了核受体TLX对前列腺癌干细胞自我更新的调控和在CRPC转化中的重要功能与机制，结果显示TLX在临床样本分离或采用谱系追踪方法分离得到的前列腺癌干细胞中显著高表达，机制研究揭示了TLX可以通过调控AR基因表达和转录，促进前列腺癌的雄激素非依赖转化的重要机制。本研究结果阐明了TLX调控前列腺癌干细胞自我更新促进CRPC进展的作用和机制，为TLX作为晚期前列腺癌治疗新靶标提供了的理论依据。