基于蛋白激酶NEK9/MTA2信号通路泛素化修饰探讨胃癌的转移机制

doi:10.3969/j.issn.1006-6233.2024.07.06

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Abstract Objective: To explore the metastasis mechanism of gastric cancer (GC) based on ubiquitination modification of the never-in-mitosis gene A-related kinase 9 (NEK9)/ metastasis-related tumor gene family 2 (MTA2) signaling pathway. Methods: The Cancer Genome Atlas (TCGA) and Kaplan-Meier Plotter databases were used to analyze the association between NEK9 expression and GC staging and prognosis. In vitro experiments, GC cells were divided into the following groups: control group, shNC group, shNEK9 group, shNC+NC-OE group, shNEK9+NC-OE group, and shNEK9+MTA2-OE group. MTT and Transwell assays were used to determine cell proliferation, migration, and invasion, respectively. Western blot was used to detect the expression of NEK9, MTA2, epithelial-mesenchymal transition (EMT) markers, and PI3K/AKT signaling pathway proteins. Results: TCGA database analysis showed that NEK9 mRNA expression was significantly upregulated in tumor tissues and was closely related to poor prognosis in patients with advanced TNM stage and high NEK9 expression. In addition, NEK9 expression was significantly higher in 7 GC cell lines compared to normal gastric epithelial GES-1 cells (P<0.05). Compared to the control group, shNEK9 group cells showed significantly decreased cell viability, relative colony formation, EdU-positive cell number, invasion, and migration (P<0.05). Moreover, E-cadherin levels were upregulated (P<0.05) and vimentin levels were downregulated (P<0.05) in shNEK9 group cells. Immunoprecipitation assay demonstrated that NEK9 interacted with MTA2. NEK9 knockdown accelerated the degradation of MTA2 in HGC-27 cells, and MTA2 ubiquitination was increased in NEK9-silenced cells. Compared to the shNEK9+NC-OE group, shNEK9+MTA2-OE group cells showed significantly increased relative colony formation, EdU-positive cell number, and migration and invasion (P<0.05). Conclusion: NEK9 is significantly upregulated in GC and its knockdown suppresses GC cell growth and metastasis in vitro. NEK9 may promote tumorigenesis in GC cells by stabilizing MTA2 through deubiquitination and activating the PI3K-AKT signaling pathway.

Key words： Gastric cancer Never in mitosis gene A-related kinase 9 Metastasis-related tumor gene family 2 Ubiquitination

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http://www.hbyxzzs.cn/EN/10.3969/j.issn.1006-6233.2024.07.06 OR http://www.hbyxzzs.cn/EN/Y2024/V30/I7/1087

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