Shao Duan-Fang, Wang Xiao-Hong, Li Zi-Yu, Xing Xiao-Fang, Cheng Xiao-Jing, Guo Ting, Du Hong, Hu Ying, Dong Bin, Ding Ning, Li Lin, Li Shen, Li Qing-Da, Wen Xian-Zi, Zhang Lian-Hai, Ji Jia-Fu
Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Institute, Peking University School of Oncology Beijing, China.
The Tissue Bank, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Cancer Hospital & Institute, Peking University School of Oncology Beijing, China.
Am J Cancer Res. 2015 Jan 15;5(2):589-602. eCollection 2015.
The SUMO pathway has been shown to play an important role in tumorigenesis. This report analyzed the involvement of the sole SUMO-Activating Enzyme Subunit 2 (SAE2) in human gastric cancer (GC) progression and prognosis.
Expression of SAE2 was examined by Quantigene Plex, western blotting and immunohistochemistry. The expression of SAE2 and c-MYC were detected in parallel in 276 cases. The molecular mechanisms of SAE2 expression and its effects on cell growth, colony formation, migration and invasion were also explored by CCK8 assay, colony formation experiment, transwell chamber assay with or without matrigel, immunoprecipitation and in vivo tumorigenesis and tumor metastasis.
SAE2 was markedly overexpressed in GC cell lines and primary tumor samples of GC, and significantly correlated with deeper tumor depth, distant metastasis, higher pathological stage and stratified survival in human GC. SAE2 positivity was independently associated with a worse outcome in multivariate analysis. Knockdown of SAE2 expression inhibited the proliferation, migration, and invasion of SAE2-overexpressing GC cells. Consistent with the in vitro results, down-regulation of SAE2 in human GC BGC823 cells significantly reduced the tumorigenic and metastatic potential of the cells in vivo. SAE2 protein was significantly associated with the higher expression of c-MYC in primary GC tissues. Moreover, FoxM1 was SUMOylated in GC and that inhibition of SAE2 resulted in a decrease in SUMO1-FoxM1 levels compared with those in the controls.
These findings suggest that SAE2 has a pivotal role in the aggressiveness of GC, and highlight its usefulness as a prognostic factor in GC.
SUMO 通路已被证明在肿瘤发生中起重要作用。本报告分析了唯一的 SUMO 激活酶亚基 2（SAE2）在人类胃癌（GC）进展和预后中的作用。
通过定量基因复合检测、蛋白质免疫印迹法和免疫组织化学检测 SAE2 的表达。在 276 例病例中平行检测 SAE2 和 c-MYC 的表达。还通过 CCK8 检测、集落形成实验、有或无基质胶的 Transwell 小室检测、免疫沉淀以及体内肿瘤发生和肿瘤转移实验，探讨了 SAE2 表达的分子机制及其对细胞生长、集落形成、迁移和侵袭的影响。
SAE2 在 GC 细胞系和 GC 原发性肿瘤样本中显著过表达，并且与人 GC 中更深的肿瘤深度、远处转移、更高的病理分期和分层生存显著相关。在多变量分析中，SAE2 阳性与更差的预后独立相关。敲低 SAE2 表达可抑制 SAE2 过表达的 GC 细胞的增殖、迁移和侵袭。与体外结果一致，人 GC BGC823 细胞中 SAE2 的下调显著降低了细胞在体内的致瘤和转移潜能。SAE2 蛋白在原发性 GC 组织中与 c-MYC 的高表达显著相关。此外，FoxM1 在 GC 中被 SUMO 化，与对照组相比，抑制 SAE2 导致 SUMO1-FoxM1 水平降低。
这些发现表明 SAE2 在 GC 的侵袭性中起关键作用，并突出了其作为 GC 预后因素的有用性。
