胃癌是中国乃至全世界范围的重大疾病负担，临床上亟需寻找分子机制明确的治疗靶点。PLK1为Polo样激酶（PLKs）家族的起始成员，与细胞周期调控及多种肿瘤发生发展相关。Ubqlns家族是一类非蛋白酶体的泛素结合蛋白，主要参与靶蛋白的泛素化降解。本项目前期研究发现在胃癌细胞中Ubqln4与PLK1存在相互作用，且Ubqln4可影响PLK1的半衰期及其泛素化降解，但具体调控机制尚不明确。基于前期基础，申请人提出假说“Ubqlns作为PLK1调控网络中的新成员参与其蛋白酶体降解途径，进而影响PLK1在胃癌发生中的作用”。本项目以Ubqln4对PLK1的影响作为切入点，通过构建内源Ubqlns与PLK1相互作用缺失的胃癌细胞模型，从分子和细胞两个水平阐明Ubqlns对PLK1泛素化降解过程的调控机制及该途径对胃癌细胞的影响，以期为胃癌的发生发展机理研究和靶向治疗提供理论依据。

Gastric cancer is a major cancer that burden in China and around the world, and it is urgent to find a clear molecular target for therapeutic purpose. PLK1, a member of the Polo-like kinase (PLKs) family, is related to cell cycle regulation and multiple tumorigenesis and development. The Ubqlns family is a class of non-proteasome ubiquitin-binding proteins. Ubqln1, Ubqln2 and Ubqln4 are commonly expressed in the human genome, which are mainly involved in the ubiquitination degradation of target proteins. Our previous study found that Ubqln4 interacts with PLK1 in gastric cancer, and affects its half-life and ubiquitination degradation, but the specific regulation mechanism is still unclear. Based on this, we hypothesize that “Ubqlns as a new member of the PLK1 regulatory network participates in PLK1’s proteasomal degradation pathway, and affects its role in the development of gastric cancer”. The study aims to start from the effect of Ubqln4 on PLK1 and reveal the mechanism that how Ubqlns family regulates PLK1 by constructing the gastric cancer cell model with endogenous Ubqlns and PLK1 interaction deletion, in order to provide theoretical foundation for the mechanism research of gastric cancer development and for the targeted intervention therapy of gastric cancer.