背景:越来越多的证据表明去泛素化酶可能有助于肿瘤进展,并且可以作为有希望的治疗靶标。
方法:通过免疫组织化学和TCGA/GO数据库分析去泛素酶OTUD6B在肺腺癌(LUAD)及其癌旁组织中的过表达。生存分析进一步支持OTUD6B作为LUAD治疗的潜在靶标。我们使用细胞活力测定和TUNEL染色评估了OTUD6B对LUAD细胞生长的影响,迁移,和侵袭实验,探讨OTUD6B对LUAD细胞凋亡和转移的影响。此外,我们在裸鼠体内建立了移植瘤模型来验证我们的发现。最后,使用IP质谱和co-IP实验,我们筛选并证实了RIPK1作为OTUD6B底物在LUAD中的影响。
结果:OTUD6B在人类LUAD中高度过表达,并预测LUAD患者的预后不良。OTUD6B敲低抑制LUAD细胞的增殖,增强凋亡,抑制LUAD细胞的转移。A549异种移植物显示OTUD6B缺失可以减缓肿瘤生长。此外,OTUD6B可以与RIPK1结合,降低其泛素化水平并增加其蛋白质稳定性。
结论:我们的结果表明,OTUD6B是LUAD治疗的一个有希望的临床靶点,靶向OTUD6B可能构成一种有效的抗LUAD策略。
BACKGROUND: There is growing evidence indicating that deubiquitinating enzymes may contribute to tumor progression and can serve as promising therapeutic targets.
METHODS: The overexpression of deubiquitinase OTUD6B in lung adenocarcinoma (LUAD) and its adjacent tissues was analyzed by immunohistochemistry and TCGA/GO database. Survival analysis further supported OTUD6B as a potential target for LUAD treatment. We assessed the effect of OTUD6B on LUAD cell growth using cell viability assays and conducted TUNEL staining, migration, and invasion experiments to investigate the impact of OTUD6B on the apoptosis and metastasis of LUAD cells. Additionally, we established a transplanted tumor model in nude mice to validate our findings in vivo. Finally, using IP mass spectrometry and co-IP experiments, we screened and confirmed the influence of RIPK1 as a substrate of OTUD6B in LUAD.
RESULTS: OTUD6B is highly overexpressed in human LUAD and predicts poor prognosis in LUAD patients. OTUD6B knockdown inhibited the proliferation of LUAD cells and enhanced apoptosis and inhibited metastasis in LUAD cells suppressed. A549 xenografts revealed that OTUD6B deletion can slow down tumour growth. Additionally, OTUD6B can bind to RIPK1, reduce its ubiquitination level and increase its protein stability.
CONCLUSIONS: Our results suggest that OTUD6B is a promising clinical target for LUAD treatment and that targeting OTUD6B may constitute an effective anti-LUAD strategy.