CK2介导Ser166磷酸化触发核转位在TRIM29“促癌”和“抑癌”功能切换中的作用及机制研究

TRIM29在肿瘤中异常表达，在不同肿瘤中可能通过组织特异性信号通路发挥“促癌”和“抑癌”作用，阐明其双重作用的机制有望为肿瘤治疗中精准靶向提供新思路和策略。最近申请者首次发现吉西他滨诱导胰腺癌细胞中TRIM29向核内转运而降低吉西他滨的抗肿瘤作用，并发现核内TRIM29表达与胰腺癌患者预后不良密切相关。申请者还发现CK2介导TRIM29在Ser166磷酸化是触发其向核内转运的必要条件，并且提示核内TRIM29可能通过糖代谢酶转录激活主要发挥“促癌”功能，而胞浆TRIM29可能通过泛素化降解JAK1主要发挥“抑癌”功能。本项目以该科学假说为主线，系统解析CK2介导TRIM29磷酸化触发其核内转运的机制及意义，并探索特异性阻断TRIM29核转运的策略，以期保留TRIM29的“抑癌”功能而阻断其“促癌”功能，为TRIM29高表达胰腺癌患者的精准治疗提供新思路和策略，具有潜在的临床应用价值。

TRIM29 is usually dysregulated in cancers and functions as both protumoral and antitumoral molecule possibly in a tissue context specific pattern. Clarifying the mechanisms underlying the obviously paradoxical function of TRIM29 may provide novel strategy for tailor treatment. Recently for the first time we found that Gemcitabine triggered nuclear translocation of TRIM29, which suppressed the antitumoral activity of Gemcitabine in pancreatic cancer. In addition, our data demonstrated that nuclear expression of TRIM29 predicted poor prognosis of patients with pancreatic cancer. Our previous data indicated that phosphorylation at Ser166 mediated by CK2 was required for nuclear translocation of TRIM29 in pancreatic cancer. In addition, our preliminary data suggested that nuclear TRIM29 may mainly function as a protumoral molecule via transactivation of glycolytic enzymes, while cytoplasmic TRIM29 may mainly function as an antitumoral molecule via ubiquitination and proteasomal degradation of JAK1. The current project aims to clarify the hypothesis by systemically analyzing the roles and mechanisms of nuclear translocation of TRIM29 in pancreatic cancer. In addition, since nuclear and cytoplasmic TRIM29 seems to function paradoxically, the current project aims to explore the strategy to specifically block nuclear translocation of TRIM29, thereby maintaining the antitumoral function of cytoplasmic TRIM29.