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浙江大学学报(医学版)  2021, Vol. 50 Issue (3): 396-402    DOI: 10.3724/zdxbyxb-2021-0146
综述     
蛋白酶体亚基对肝细胞癌发生发展的调控作用研究进展
胡靖依(),王青青,刘杨()
浙江大学医学院免疫学研究所,浙江 杭州 310058
Research progress on proteasome subunits in regulating occurrence and development of hepatocellular carcinoma
HU Jingyi(),WANG Qingqing,LIU Yang()
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
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摘要:

蛋白酶体是真核细胞中负责降解细胞内短寿命蛋白、参与维持细胞内蛋白质稳态的重要细胞器。研究表明,在肝细胞癌(HCC)的发生发展进程中,蛋白酶体调节颗粒亚基可通过调节PTEN基因、P53、Bcl-2、Bcl-2相互作用的细胞死亡介体蛋白、周期蛋白依赖性激酶4、β型转化生长因子受体、E2F1、生长因子受体结合蛋白2等多种肿瘤相关蛋白以及相关的通路分子,例如信号转导及转录激活蛋白3、蛋白激酶B,诱使这些蛋白质功能失调,进而促进HCC的发生,癌细胞增殖、侵袭与转移。蛋白酶体核心颗粒亚基则更多参与HCC相关蛋白的降解,因此核心颗粒的抑制剂表现出良好的抗肿瘤效应。本文就当前蛋白酶体调节颗粒亚基和核心颗粒亚基在HCC发生发展过程中的调控作用及其机制进行综述。

关键词: 蛋白酶体蛋白酶体调节颗粒蛋白酶体核心颗粒肝细胞癌机制综述    
Abstract:

Proteasome is the eukaryotic organelle responsible for degradation of short-lived proteins and involved in maintaining cellular protein homeostasis. It has been reported that during the occurrence and development of hepatocellular carcinoma (HCC), the regulatory particle subunits of proteasome regulate a series of tumor-related proteins, and proliferation, survival-associated signaling molecules, including PTEN gene, P53, Bcl-2, Bcl-2 interacting mediator of cell death (Bim), cyclin-dependent kinase 4(CDK4), transforming growth factor β receptor (TGFBR), E2F1, growth factor receptor-bound protein 2 (GRB2) . Meanwhile, these subunits regulate some tumor-associated pathway protein, such as signal transducer and activator of transcription 3 (STAT3) and protein kinase B (AKT), inducing their malfunction to promote the occurrence, proliferation, invasion and metastasis of HCC. The core particle subunits are more to perform the degradation of HCC-related proteins, so inhibitors targeting the core particle show a good anti-tumor effect. This review summarizes the current research progress on the regulation and mechanism of proteasome subunits in promoting the occurrence and development of HCC.

Key words: Proteasome    Proteasome regulatory particle    Proteasome core particle    Hepatocellular carcinoma    Mechanism    Review
收稿日期: 2021-01-11 出版日期: 2021-08-16
CLC:  R735.7  
基金资助: 国家自然科学基金(81872248)
通讯作者: 刘杨     E-mail: hjy558@zju.edu.cn;liuyang0620@zju.edu.cn
作者简介: 胡靖依,硕士研究生,主要从事肿瘤免疫与抗病毒天然免疫研究;E-mail:hjy558@zju.edu.cn;https://orcid.org/0000-0002-8708-4037
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引用本文:

胡靖依,王青青,刘杨. 蛋白酶体亚基对肝细胞癌发生发展的调控作用研究进展[J]. 浙江大学学报(医学版), 2021, 50(3): 396-402.

HU Jingyi,WANG Qingqing,LIU Yang. Research progress on proteasome subunits in regulating occurrence and development of hepatocellular carcinoma. J Zhejiang Univ (Med Sci), 2021, 50(3): 396-402.

链接本文:

http://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2021-0146        http://www.zjujournals.com/med/CN/Y2021/V50/I3/396

图 1  蛋白酶体调节颗粒亚基在HCC中的作用机制在肝细胞癌(HCC)细胞内,蛋白酶体调节颗粒亚基通过不同的机制发挥作用. “盖子”亚基:调节颗粒非ATP酶亚基(Rpn)11通过对生长因子受体结合蛋白2(GRB2)、 P53、Bcl-2相互作用的细胞死亡介体蛋白(Bim)以及E2F1的去泛素化修饰,不断激活细胞内的存活和增殖信号,促进HCC的发生. 其中,Rpn11对小窝蛋白和β型转化生长因子受体(TGFBR)的去泛素化修饰抑制了网格蛋白介导的对TGFBR的内吞作用,进而抑制TGFBR经溶酶体途径的降解,使TGFBR持续发挥作用,从而促进HCC的转移. “底座”亚基:①Gankyrin直接扰乱了周期蛋白依赖性激酶4(CDK4)的折叠进程,造成大量CDK4在细胞质内累积,直接催化结合了E2F1的视网膜细胞瘤基因蛋白(Rb)的磷酸化,Rb磷酸化后释放出E2F1入核,直接诱导细胞周期相关基因的转录,促进HCC细胞增殖;Gankyrin也可以自身作为一种转录因子,转位入核诱导自噬相关基因7(ATG7)的转录,增强HCC细胞的自噬功能,进而促进肿瘤细胞存活;Gankyrin还可以与肉瘤酪氨酸激酶同源区2-蛋白酪氨酸磷酸酶 1(SHP-1)相互作用,活化信号转导及转录激活蛋白3(STAT3)通路,或直接活化磷脂酰肌醇3激酶/蛋白激酶B(PI3K/AKT)信号通路,促进HCC增殖. ②Rpn10不仅可以上调癌基因蛋白环氧合酶2(COX-2)、Bcl-2和磷酸化肉瘤酪氨酸激酶(p-SRC)的表达,还可促进抑癌基因蛋白PTEN的降解. ③Rpn1和Rpn2则可通过增强细胞脂质代谢促进HCC发生、癌细胞增殖和转移.
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