促炎激酶TNFα调控雄激素受体在前列腺癌进展中的表观遗传学机制研究

Nearly all men with prostate cancer develop a resistant state known as Castration- Resistant Prostate Cancer (CRPC) after androgen deprivation therapy (ADT), which is presently incurable and accounts for most PCa mortality. Previous studies have shown that androgen receptor dysregulation is partly attributed to TNFα resistance, which is also lacking details of the molecular mechanism. Preliminary study firstly uncovered the negative correlation between the intensity of AR protein level and inflammatory infiltration in patients of PCa. Moreover, to some extent, pro-inflammatory cytokine TNFα directly regulates post-translational modification of AR in Androgen-dependent Prostate Cancer (ADPC) but not in CRPC in vitro experiment. Herein, to thoroughly elucidate the mechanism how TNFα regulates AR, the study illuminates the exploration of specific phosphorylation site(s) of AR by IKKβ activated via TNFα, which contributes to expose the aberrant molecular mechanism in the progression of CRPC.Our research strives to look for a bona fide target downstream of TNFα signaling pathway, aiming to unravel the promising mechanism of CRPC.

前列腺癌经雄激素剥夺治疗后，几乎所有患者都会对抗雄治疗产生抵抗，进展为去势抵抗性前列腺癌（CRPC），因其难以治愈，严重威胁患者的生命健康。前期研究表明，在CRPC进展过程中，肿瘤坏死因子TNFα失敏感导致AR调节紊乱，然而其具体机制仍不清楚。本课题组首次在前列腺癌患者标本中发现炎症渗透与AR表达存在负相关，且体外实验初步证实:在激素依赖性前列腺癌（ADPC）中，促炎激酶TNFα在一定程度上直接以翻译后修饰方式调节AR的蛋白水平，而对CRPC中AR失调节。在此基础上，揭示ADPC中TNFα如何调节AR，探明TNFα激活IKKβ并磷酸化AR的特异性作用位点，有助于阐明CRPC进展过程中的异常改变的分子机制，并针对TNFα信号通路，寻找下游新的靶点，为CRPC患者的治疗寻找新靶点，阐述新机制。

雄激素受体(AR)是前列腺癌的主要生存因素。炎症与许多类型的癌症有关，包括前列腺癌。MAP3K7(TAK1)和下游IKKb通过促炎细胞因子如TNFa激活NF-kB信号通路。矛盾的是，MAP3K7在人类前列腺癌中经常缺失。我们证明了AR蛋白在前列腺癌患者炎症性肿瘤区域的表达低于非炎症性组织。Map3k7敲除增加了小鼠前列腺AR蛋白水平和活性，并且Map3k7和AR蛋白水平在前列腺癌患者标本中呈负相关。TNFa刺激增加了AR蛋白泛素化和蛋白酶体降解。从机制上讲，TNFa激活IKKb诱导了AR蛋白的磷酸化和TRCP1/2 E3连接酶介导的多聚泛素染色和降解。TNFa抑制前列腺癌的增殖，可通过阻断AR的降解来挽救。这些发现揭示了炎症激活的MAP3K7-IKKb轴在降解AR蛋白中的一种新的肿瘤抑制功能。此外，认为AR蛋白的异常升高可能是map3k7缺失前列腺癌的一个重要的生物标志物和治疗靶点。