泛素特异性蛋白酶在肝细胞癌中的作用

唐怡; 王国泰; 蒋雨涵

doi:10.12449/JCH250525

泛素特异性蛋白酶在肝细胞癌中的作用

DOI: 10.12449/JCH250525

唐怡¹,
王国泰^2, , ,,
蒋雨涵¹

1.
陕西中医药大学第一临床医学院，陕西咸阳 712046
2.
陕西中医药大学附属医院肝胆外科，陕西咸阳 712099

基金项目:

陕西省中医药管理局 (SZY-KJCYC-2025-JC-004);

秦创原中医药产业创新聚集区项目 (L2024-QCY-ZYYJJQ-Y09);

咸阳市中青年科技领军人才项目 (L2022CXNLRC018);

咸阳市科学技术局 (2021ZDYF-SF-0037)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：唐怡负责资料分析，撰写论文；王国泰负责分析相关材料，并修改论文；蒋雨涵负责检索和收集相关文献。

详细信息

通信作者:
王国泰， wangtai_52@126.com （ORCID： 0009-0009-5405-9351）

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出版历程
- 收稿日期: 2024-09-13
- 录用日期: 2024-11-08
- 出版日期: 2025-05-25

Role of ubiquitin-specific proteases in hepatocellular carcinoma

Yi TANG¹,
Guotai WANG^{2
, ,
,},
Yuhan JIANG¹

1.
The First Clinical Medical College，Shaanxi University of Chinese Medicine，Xianyang，Shaanxi 712046，China
2.
Department of Hepatobiliary Surgery，The Affiliated Hospital of Shaanxi University of Chinese Medicine，Xianyang，Shaanxi 712099，China

Research funding:

Shaanxi Administration of Traditional Chinese Medicine (SZY-KJCYC-2025-JC-004);

Qinchuangyuan Traditional Chinese Medicine Industry Innovation Cluster Project (L2024-QCY-ZYYJJQ-Y09);

Project for Young and Middle-aged Science and Technology Leaders in Xianyang City (L2022CXNLRC018);

Xianyang Science and Technology Bureau (2021ZDYF-SF-0037)

More Information

Corresponding author: WANG Guotai， wangtai_52@126.com （ORCID： 0009-0009-5405-9351）

摘要

摘要: 肝细胞癌（HCC）是一种常见的原发性恶性肿瘤。近年来，泛素特异性蛋白酶（USP）在HCC中的作用引起了广泛关注。USP是一类关键的去泛素化酶，通过调节蛋白质的泛素化状态，影响多种生物学过程。研究发现，USP通过去泛素化多种肿瘤相关蛋白，参与调控细胞增殖、凋亡、迁移和侵袭等过程。此外，USP的异常表达与HCC患者的预后密切相关，可能作为潜在的生物标志物和治疗靶点。本文综述了USP在HCC中的研究进展，探讨了USP在HCC发生、发展及转移中的关键作用。深入了解USP在HCC中的作用机制，不仅有助于揭示HCC的发病机理，也为开发新的诊断工具和治疗策略提供了科学依据。未来的研究应进一步探索USP在HCC中的调控作用，以期为HCC的临床治疗提供更多有效手段。
- 癌，肝细胞 /
- 泛素特异性蛋白酶类 /
- 酶抑制剂
Abstract: Hepatocellular carcinoma （HCC） is a common primary malignant tumor. In recent years， the role of ubiquitin-specific proteases （USPs） in HCC has attracted widespread attention. USPs are a class of key deubiquitinating enzymes that affect a variety of biological processes by regulating the ubiquitination status of proteins. Studies have shown that USPs participate in the regulation of cell proliferation， apoptosis， migration， and invasion by deubiquitinating various tumor-related proteins. In addition， the abnormal expression of USPs is closely associated with the prognosis of HCC patients and may thus be used as potential biomarkers and therapeutic targets. This article reviews the research advances in USPs in HCC and explores their key roles in the development， progression， and metastasis of HCC. A deep understanding of the mechanism of action of USPs in HCC not only helps to reveal the pathogenesis of HCC， but also provides a scientific basis for developing new diagnostic tools and treatment strategies. Future research should further explore the regulatory effect of USPs in HCC， in order to provide more effective means for the clinical treatment of HCC.
- Carcinoma， Hepatocellular /
- Ubiquitin-Specific Proteases /
- Enzyme Inhibitors

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注： N-RAS，神经母细胞瘤RAS病毒癌基因同源物；HGF，肝细胞生长因子；TCF/LEF，T细胞因子/淋巴增强因子；TEAD，TEA结构域转录因子；LRP，低密度脂蛋白受体相关蛋白；Frizzled，卷曲蛋白。YAP/TAZ信号通路，USP1与USP10通过去泛素化和稳定YAP/TAZ来促进HCC的增殖，增强了YAP/TAZ在HCC细胞中的致癌功能^{［ 4， 14］}。PI3K/AKT信号通路，USP35通过去泛素化稳定ABHD17C，从而激活N-RAS并通过PI3K/AKT信号通路促进HCC细胞的增殖、迁移和侵袭^{［ 30］}。USP11阻止了eEF1A1的降解，促进SP1与HGF基因启动子的结合，增加HGF的表达，进而激活PI3K/AKT信号通路^{［ 15］}。Wnt/β-catenin信号通路，USP8通过稳定β-catenin蛋白，从而激活Wnt/β-catenin信号通路^{［ 12］}。USP25通过Wnt/β-catenin信号通路与TRIM21相互作用，促进HCC进展^{［ 26］}。

图 1 DUB在HCC YAP/TAZ、PI3K/AKT和Wnt/β-catenin信号通路中的作用

Figure 1. The role of DUB in the YAP/TAZ， PI3K/AKT， and Wnt/β-catenin signaling pathways in hepatocellular carcinoma

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表 1 HCC相关USP

Table 1. USP associated with hepatocellular carcinoma

USP	靶蛋白	信号通路	在HCC中的作用	参考文献
USP1	未明确	YAP/TAZ	生长、转移	［4］
USP2a	RAB1A	未明确	增殖、迁移、侵袭	［5］
USP4	CypA	MAPK	生长、迁移、侵袭	［6］
USP4	TGF-βR1	TGF-β	侵袭、转移	［7］
USP5	SLC7A11	未明确	铁死亡	［8］
USP5	SLUG	未明确	增殖、转移、侵袭	［9］
USP7	TRIP12	未明确	增殖、迁移、侵袭	［10］
USP7	STAT3	未明确	增殖、转移	［11］
USP8	未明确	Wnt/β-catenin	增殖、迁移、侵袭、铁死亡	［12］
USP10	Smad4	TGF-β	转移	［13］
USP10	YAP/TAZ	YAP/TAZ	增殖、迁移	［14］
USP11	eEF1A1	PI3K/AKT	EMT、转移	［15］
	HIF-1α	未明确	糖酵解、增殖、转移	［16］
	NF90	未明确	增殖、转移	［17］
USP12	未明确	MAPK	细胞凋亡	［18］
USP13	TLR4	TLR4/MyD88/NF-κB	增殖、迁移、侵袭	［19］
USP14	SQSTM1	未明确	自噬、增殖、侵袭、细胞凋亡	［20］
USP14	HIF-1α	未明确	迁移、侵袭	［21］
USP19	YAP	Hippo	增殖、迁移	［22］
USP21	MEK2	ERK	生长、增殖	［23］
USP22	E2F6	AKT	生长	［24］
USP22	HIF-1α	未明确	细胞干性、糖酵解	［25］
USP25	TRIM21	Wnt/β-catenin	增殖、迁移、侵袭、EMT	［26］
USP27	SETD3	未明确	生长、增殖、迁移	［27］
USP29	HIF-1α	未明确	糖酵解、耐药性	［28］
USP35	PKM2	未明确	增殖、迁移、侵袭	［29］
USP35	ABHD17C	PI3K/AKT	生长、增殖、迁移	［30］
USP39	SP1	未明确	增殖	［31］
USP40	YAP	未明确	增殖、迁移	［32］
USP46	MST1/YAP	未明确	增殖、转移	［33］
注：YAP/TAZ，Yes相关蛋白/PDZ结合基序转录共激活因子；RAB1A，Ras相关蛋白Rab-1A；CypA，亲环蛋白A；MAPK，丝裂原活化蛋白激酶；TGF-βR1，转化生长因子β受体1；SLC7A11，溶质载体家族7成员11；SLUG，锌指蛋白SNAI2；TRIP12，甲状腺激素受体相互作用蛋白12；STAT3，信号转导及转录激活因子3；Wnt/β-catenin，Wnt信号通路/β-连环蛋白；Smad4，SMAD家族成员4；eEF1A1，真核翻译延伸因子1A1；PI3K/AKT，磷脂酰肌醇3-激酶/蛋白激酶B；EMT，上皮-间充质转化；HIF-1α，缺氧诱导因子-1α；NF90，核因子90；MyD88，髓样分化因子88；SQSTM1，序列相似性家族62成员1；MEK2，丝裂原活化蛋白激酶激酶2；ERK，细胞外信号调节激酶；E2F6，E2F转录因子6；TRIM21，三结构域蛋白21；SETD3，SET结构域包含蛋白3；PKM2，丙酮酸激酶M2；ABHD17C，α/β水解酶结构域蛋白17C；SP1，特异性蛋白1；MST1，哺乳动物STE20样激酶1。

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