前列腺癌干细胞雄激素受体甲基化在前列腺癌进展中分子机制的研究

项目名称： 前列腺癌干细胞雄激素受体甲基化在前列腺癌进展中分子机制的研究

项目编号： No.81202024

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 田晶

作者单位： 天津医科大学

项目金额： 23万元

中文摘要： 非激素依赖性前列腺癌是前列腺癌进展的最终阶段，干细胞可能是前列腺癌恶性进展的核心问题。雄激素受体介导的信号通路是前列腺癌发生发展的中心环节，但对前列腺癌干细胞的影响机制尚不清楚。我们前期研究发现AR在永生化的前列腺癌干细胞系中表达缺失，由AR启动子区CpG岛高度甲基化抑制AR的转录所致，推测其可能为导致ADT治疗失败的重要原因。本研究试图从四个层面进行研究：(1)从人前列癌细胞系、PCa动物模型移植瘤及人肿瘤组织中分离出前列腺癌干细胞并研究其生物学特性；(2)进一步探索AR对前列腺癌干细胞的调节作用；(3)阐明AR启动子高度甲基化沉默其在干细胞中表达的分子机制，(4)通过应用甲基化酶抑制剂5-Aza-2'-deoxycytidine使干细胞AR去甲基化，进一步观察干细胞特性的变化。揭示AR 启动子DNA甲基化在前列腺癌进展中调节的分子机制，为前列腺癌干细胞靶向治疗提供科学依据和新思路。

中文关键词： 前列腺癌；前列腺癌干细胞；雄激素受体；DNA甲基化；表观遗传学调节

英文摘要： Androgen independent prostate cancer is the last stage in prostate cancer and prostate cancer stem cells play an important role in prostate cancer progress.Androgen/androgen receptor pathway is a key link in progressive prostate cancer,but the molecular mechanism still not clear. In our provious studies, we found that AR no expression in immortalized prostate cancer stem cell line PCSC due to many CpG island methylated in AR promotor. AR DNA methylation status inhibited AR transcription and expression. We speculate that it may be the root cause of ADT treatment failure.Therefore, we try to isolate the populations of prostate cancer stem cells from prostate cancer cell lines, LNCaP xenograft mouse model and human prostate cancer tissue three different sources and identify their stemness biological characteristics. Explore the AR role in prostate cancer stem cells and investigate the process of their epigenetic modification.To further study on AR in maintenance of epigenetic regulation of prostate cancer stem cell properties, and the molecular mechanism concerning the progressive prostate cancer.We observe the biological feature changing of prostate cancer stem cells after DNA transferase inhibitor 5-Aza-2'-deoxycytidine treatment. Our goal is to provide experimental evidence and novalty idea to support the target

英文关键词： prostate cancer；prostate cancer stem cell；androgen receptor；DNA methylation；Epigenitic Modification