AR及Wnt/β-catenin通路调控血小板活化因子参与去势耐受型前列腺癌形成及其机制研究

项目名称： AR及Wnt/β-catenin通路调控血小板活化因子参与去势耐受型前列腺癌形成及其机制研究

项目编号： No.81472398

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 徐斌

作者单位： 中国人民解放军第二军医大学

项目金额： 68万元

中文摘要： 雄激素剥夺是晚期前列腺癌（PCa）主要治疗方法，但经一定时间治疗后几乎所有PCa都将转变为去势耐受型前列腺癌（CRPC）导致抗雄治疗无效,其机制未明。我们前期研究发现PCa细胞内血小板激活因子（PAF）合成酶LPCAT较正常前列腺细胞表达明显增强；PCa细胞进入CRPC期后LPCAT和PAF表达进一步升高；PAF增加促进PCa细胞侵袭和转移；进一步实验提示CRPC形成前后雄激素可能通过AR或Wnt/β-catenin分别调控PAF。本课题拟在此基础上，进一步揭示雄激素调控PAF参与PCa发生发展的基因组和非基因组机制，揭示PAF在抗雄后CRPC形成中的重要作用。通过动物模型研究阻断PAF或其信号通路关键分子对前列腺癌细胞生长、侵袭、转移能力影响，研究靶向PAF治疗PCa尤其是预防和治疗抗雄后CRPC侵袭性表型形成的可行性。课题开展有利于进一步揭示CRPC形成机制并为CRPC治疗提供新思路。

中文关键词： 前列腺癌；去势耐受型前列腺癌；雄激素受体；血小板活化因子；Wnt/β-catenin

英文摘要： Androgen deprivation therapy (ADT) is generally employed for the treatment of advanced or metastatic prostate cancer (PCa), however, prostate cancer cells eventually show no response to ADT, and acquire an castration-resistant phenotype at a certain stage, which is referred to as castration-resistant prostate cancer (CRPC).The mechanisms underlying the emergence of CRPC are still not clearly identified. The present group found the expression of PAF synthetase, lyso-PAF acetyl transferase (LPCAT), in PCa cells, was stronger than that in normal prostate cells. It was also found that the expression of LPCAT increased in CRPC specimens, consistent with higher level of PAF in CRPC cell line PC-3 than in androgen-dependent prostate cancer cell line LNCaP. PAF induced invasion and migration of PCa cells. Dihydrotestosterone (DHT) treatment caused a decrease in LPCAT expression and PAF release in LNCaP cells. By contrast, DHT may increase LPCAT expression and PAF release in PC-3 cells in a Wnt/?-catenin-dependent manner. Based on our previous results, the aim of the present study is to investigate possible signaling pathways mediating genomic or non-genomic effects of androgen on PAF production in the emergence and development of PCa, and to discover the important role of PAF in the emergence of CRPC after ADT. Furthermore, in animal model, we will investigate the effect of blockade of PAF or the key factor of the PAF pathway on the biological action of PCa cells, to clarify the feasibility of PAF-target treatment on prevention and inhibition of aggressive phenotype of CRPC after ADT. The present study may contribute to identify the mechanisms underlying the emergence of CRPC and lead to new strategies to neutralize aggressive CRPC.

英文关键词： PCa;CRPC;AR;PAF;Wnt/β-catenin