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

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.

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。

我们前期的研究表明，与原发性前列腺癌(PCa)相比，溶磷脂酰胆碱酰转移酶(LPCAT1)在去势抵抗型前列腺癌(CRPC)中过表达，并其表达受雄激素调控的wnt信号通路调控。然而，其在CRPC进展中的作用尚不清楚。本研究旨在探讨LPCAT1在CRPC进展中的作用及其分子机制。研究发现LPCAT1在体外和体内水平均可促进CRPC的增殖，迁移和侵袭。LPCAT1沉默可使CRPC细胞侵袭和迁移能力减低，但血小板活化因子乙酰水解酶(PAF-AH)和PAFR拮抗剂ABT-49可逆转这一现象；外源性PAF可逆转LPCAT1过表达诱导CRPC细胞侵袭和迁移能力增加。然而LPCAT1诱导的细胞增殖能力增加或者减弱的不受PAF-AH或外源性PAF的影响。LPCAT1以雄激素依赖性的方式进入细胞核促使组蛋白H4棕榈酰化，从而增加mRNA合成，促进CRPC细胞生长。此外，我们研究发现过表达LPCAT1可损害CRPC细胞对化疗药物紫杉醇的敏感性。以上这些结果显示LPCAT1可能是CRPC患者治疗的一个潜在靶标，这需要我们对其促进CRPC进展的机制进行深入探索。