ANT-1调控雄激素受体与其变异体介导基因转录的机制及其在前列腺癌的作用研究

Androgen receptor (AR) recruits a series of co-regulators in regulating AR-mediated gene transcription. During this process, defects in functional regulation of AR and its variant AR-V7 play important role in development of prostate cancer (PCa) and especially castration-resistant prostate cancer (CRPC), so that analysis on effect and mechanism of AR/AR-V7 is essential for deeper understanding the mechanism for the onset of PCa/CRPC. We performed bioinformatical method and found a series of essentially highly expressed genes in CRPC compared with PCa. Our former experimental results confimed within these factors ANT-1 separately promoted AR or AR-V7 mediated gene transcription and formation of AR-V7, and meanwhile ANT-1 promoted develepment of PCa/CRPC cells. This project will further study the AR-mediated gene expression and molecular mechanism for formation of AR-V7 under the basis of stating the effect of ANT-1 on regulating AR/AR-V7 mediated gene transcription, and moreover deeply study the effect and mechanism of ANT-1 on PCa progression, CRPC tranversion as well as tumor invasion and metastasis, and thus provide theoretical basis and new target for early diagnosis and treatment of PCa and CRPC.

雄激素受体（AR）招募一系列辅调节因子参与调控AR介导的基因转录，AR及其变异体AR-V7功能调控的异常在前列腺癌（PCa）特别是去势抵抗性前列腺癌(CRPC) 发生发展过程中发挥重要作用，因此鉴定和解析AR/AR-V7辅调节因子的作用及机制将有助于阐明PCa/CRPC发病机制。我们通过生物信息学分析发现一系列在CRPC相对PCa有显著高表达并参与AR介导基因转录调控的因子。前期实验结果证实上述因子中ANT-1分别促进AR或AR-V7介导的基因转录以及AR-V7的形成，同时ANT-1促进PCa/CRPC细胞的生长。本项目将在明确ANT-1调控AR/AR-V7介导基因转录基础上，进一步解析ANT-1调控AR介导基因转录和AR-V7形成的分子机制，并深入研究ANT-1在PCa进程、CRPC转化进程及肿瘤侵袭转移等方面的作用及其分子机制，为PCa和CRPC早期诊断和治疗提供理论依据和新靶点。

雄激素受体（AR）招募一系列辅调节因子参与调控AR介导的基因转录，AR及其变异体AR-V7功能调控的异常在PCa, 特别是去势抵抗性前列腺癌(CRPC) 发生发展过程中发挥重要作用，因此鉴定和解析AR/AR-V7辅调节因子的作用及机制将有助于阐明PCa/CRPC发病机制，并为其治疗提供新策略。我们前期通过生物信息学方法对CRPC与PCa细胞系中的基因表达进行分析，发现一系列在CRPC中有显著高表达并参与AR介导基因转录调控的因子。我们的实验结果证实上述因子中作为剪接因子ANT-1分别促进AR或AR-V7介导的基因转录；重要的是，ANT-1促进了AR-V7的剪接形成。此外，我们检测到ANT-1能促进PCa/CRPC细胞的生长。本项目明确了ANT-1调控AR/AR-V7介导基因转录基础上，进一步解析ANT-1调控AR介导基因转录的分子机制，特别将深入阐明ANT-1在AR-V7剪接形成的作用及机制，并深入研究ANT-1在前列腺癌进程、CRPC转化进程及肿瘤侵袭转移等方面的作用及其分子机制，为该疾病的早期诊断和治疗提供理论依据和新靶点。并利用ANT-1的蛋白质谱发现了新的ANT-1相关的五个前列腺癌去势抵抗的驱动因子和相关药物，为进一步解明去势抵抗的机制提供依据。