LRPPRC通过泛表达蛋白UXT调控雄激素受体的自噬降解而影响CRPC形成的研究

前列腺癌（PCa）是全球男性主要致死性肿瘤之一，形成去势抵抗性前列腺癌（CRPC）是其主要致死原因但其形成机制尚不明确。雄激素受体（AR）的累积是PCa在去势所致持续低水平雄激素微环境中仍能不断生长的关键，而CRPC细胞中确实存在因自噬降解受阻而高水平表达的AR。申请人前期研究发现在PCa中自噬抑制蛋白LRPPRC高表达会造成自噬抑制和不良预后，另研究表明泛表达蛋白UXT低表达亦与PCa不良预后相关，在PCa中UXT与AR互作且共分布于胞核有助于将AR送至自噬体降解，然而在CRPC中UXT却主要分布于胞质。我们已在COS7细胞中证实UXT与LRPPRC存在互作，基于此本项目提出LRPPRC通过与UXT胞质结合会抑制AR经自噬降解而促进CRPC形成的假设，我们拟通过临床标本、去势诱导CRPC动物模型等观察上述关键蛋白动态变化，旨在揭示CRPC形成的可能机制，为临床治疗及开发新靶标提供思路。

Prostate cancer (PCa) is one of the leading causes of cancer death among men worldwide, and the mechanism for its development to castration-resistant prostate cancer (CRPC) is unclear. The accumulation of androgen receptor (AR) is the key for PCa to maintain normal function and promote PCa growth in the microenvironment where exists constant low-levels of androgen induced by castration. In addition, CRPC cells have high levels of AR and an impaired autophagy degradation of AR. The applicants found that both accumulation of autophagy inhibitory protein LRPPRC promoted the development of PCa and CRPC and predicted a poor prognosis for PCa patients, and other studies have shown that UXT also predicted a poor prognosis for PCa patients, and interacted and co-distributed with AR in the nucleus of PCa cells are beneficial to the autophagy degration of AR, but UXT disassociated from nuclear AR and migrated to cytosol in recurrent PCa. Since we have proved that LRPPRC interacts with UXT in COS7 cells, it is proposed here that LRPPRC suppresses autophagy degradation of AR and promotes the development of CRPC through UXT. We aim to observe the real-time dynamic changes of proteins mentioned above via clinical samples, castration induced mice models and so on, revealing such a possible mechanism will provide new ideas for clinical treatment of CRPC and development of new therapeutic targets.