雄激素受体依赖的胶质母细胞瘤自分泌睾酮的机制研究

Androgen receptor (AR) is highly expressed in glioblastoma multiforme (GBM), which is closely related to the progression of GBM, but the source of the androgen is still uncertain. It has been reported that CYP17A1, the testosterone-producing rate-limiting enzyme, expressing in GBM suggesting that testosterone is synthesized from cholesterol in GBM cells. A transcription factor sterol-regulatory element binding protein 2 (SREBP2) regulates the production of cholesterol in GBM. Our recent research indicated that the testosterone concentration in cerebral fluid is higher than that in blood of GBM patients, but on the contrary, it is lower in cerebral fluid than in blood of normal people. SREBP2 is highly expressed in GBM and over-expression of which remarkably increases the transcriptional level of CYP17A1, but the regulatory mechanism is unclear. Base on the facts above, we plan to perform the study as below: 1) to prove that testosterone is synthesized by GBM cells; 2) to prove that SREBP2 is the transcription factor to CYP17A1 with luciferase reporter gene assay, chromatin immunoprecipitation and electrophoretic mobility shift assay; to prove that SREBP2-CYP17A1-AR pathway regulates the growth of GBM in vitro and in vivo; to test whether a synergistic effect on GBM growth inhibition exists when combining use of CYP17A1 inhibitor and HMGCR, a rate-limiting enzyme in cholesterol production, inhibitors. This research will not only further unveil the mechanism of GBM growth, but also provide a theoretical basis for the design of new strategy against androgen producing.

胶质母细胞瘤（GBM）中雄激素受体（AR）表达异常升高与GBM进展密切相关，但雄激素来源不明。有研究显示GBM表达睾酮合成限速酶CYP17A1，提示GBM可能利用胆固醇自身合成睾酮。转录因子胆固醇调节元件结合蛋白2（SREBP2）调节GBM胆固醇合成。我们在近期研究中发现GBM患者睾酮水平脑脊液>血液，而正常人与之相反；SREBP2在GBM样本中高表达，SREBP2过表达显著增加CYP17A1转录，但具体调节机制仍不清楚。在此基础上拟开展以下研究：证明GBM自身合成睾酮；荧光素酶报告基因、染色质免疫沉淀及电泳迁移实验证明SREBP2是CYP17A1的转录因子；体外及体内实验证明SREBP2-CYP17A1-AR途径调节GBM生长；CYP17A1与胆固醇合成限速酶HMGCR的抑制剂联合用药是否对抑制GBM细胞生长具有协同作用。研究将进一步揭示GBM生长机制并为开发抑制雄激素合成新策略提供依据

胶质母细胞瘤（GBM）中雄激素受体（AR）表达异常升高与GBM进展密切相关，但雄激素来源不明。有研究显示GBM表达睾酮合成限速酶CYP17A1，提示GBM可能利用胆固醇自身合成睾酮。转录因子胆固醇调节元件结合蛋白2（SREBP2）调节GBM胆固醇合成。我们在近期研究中发现GBM患者睾酮水平脑脊液>血液，而正常人与之相反；SREBP2在GBM样本中高表达，SREBP2过表达显著增加CYP17A1转录，但具体调节机制仍不清楚。在此基础上本研究开展以下内容：证明GBM自身合成睾酮；荧光素酶报告基因、染色质免疫沉淀及电泳迁移实验证明SREBP2是CYP17A1的转录因子；体外及体内实验证明SREBP2-CYP17A1-AR途径调节GBM生长；CYP17A1与胆固醇合成限速酶HMGCR的抑制剂联合用药是否对抑制GBM细胞生长具有协同作用。研究揭示GBM生长机制并为开发抑制雄激素合成新策略提供依据。