UCHL3 通过去泛素化稳定 EEF1A1 促进肝细胞癌进展。

UCHL3 promotes hepatocellular carcinoma progression by stabilizing EEF1A1 through deubiquitination.

机构信息

College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.

Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, China.

出版信息

Biol Direct. 2024 Jul 4;19(1):53. doi: 10.1186/s13062-024-00495-w.

DOI:10.1186/s13062-024-00495-w

PMID:38965582

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11225194/

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) ranks as the second leading cause of global cancer-related deaths and is characterized by a poor prognosis. Eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) have been proved to play important roles in various human cancers, whereas the deubiquitination of EEF1A1 was poorly understood.

METHODS

The binding and regulatory relationship between Ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) and EEF1A1 was validated using clinical tissue samples, reverse transcription quantitative real-time fluorescence quantitative PCR (RT-qPCR), Western blotting, co-immunoprecipitation, and immunofluorescence, as well as ubiquitin detection and cyclohexamide tracking experiments. Finally, the impact of the UCHL3/EEF1A1 axis on HCC malignant behavior was analyzed through functional experiments and nude mouse models.

RESULTS

UCHL3 was found to have a high expression level in HCC tissues. Tissue samples from 60 HCC patients were used to evaluate the correlation between UCHL3 and EEF1A1. UCHL3 binds to EEF1A1 through the lysine site, which reduces the ubiquitination level of EEF1A1. Functional experiments and nude mouse models have demonstrated that the UCHL3/EEF1A1 axis promotes the migration, stemness, and drug resistance of HCC cells. Reducing the expression of EEF1A1 can reverse the effect of UCHL3 on the malignant behavior of HCC cells.

CONCLUSION

Our findings revealed that UCHL3 binds and stabilizes EEF1A1 through deubiquitination. UCHL3 and EEF1A1 formed a functional axis in facilitating the malignant progression of HCC, proving new insights for the anti-tumor targeted therapy for HCC.

摘要

背景

肝细胞癌（HCC）是全球癌症相关死亡的第二大主要原因，其预后较差。真核翻译延伸因子 1 阿尔法 1（EEF1A1）已被证明在各种人类癌症中发挥重要作用，而 EEF1A1 的去泛素化作用知之甚少。

方法

使用临床组织样本、逆转录定量实时荧光定量 PCR（RT-qPCR）、Western blot、免疫共沉淀和免疫荧光以及泛素检测和环己酰亚胺追踪实验验证了泛素羧基末端水解酶 L3（UCHL3）和 EEF1A1 之间的结合和调节关系。最后，通过功能实验和裸鼠模型分析了 UCHL3/EEF1A1 轴对 HCC 恶性行为的影响。

结果

UCHL3 在 HCC 组织中表达水平较高。使用 60 例 HCC 患者的组织样本评估 UCHL3 与 EEF1A1 之间的相关性。UCHL3 通过赖氨酸位点与 EEF1A1 结合，从而降低 EEF1A1 的泛素化水平。功能实验和裸鼠模型表明，UCHL3/EEF1A1 轴促进了 HCC 细胞的迁移、干性和耐药性。降低 EEF1A1 的表达可以逆转 UCHL3 对 HCC 细胞恶性行为的影响。