热休克蛋白gp96在恶性肿瘤中的研究进展  

Research Progress of The Role of Heat Shock Protein gp96 in Cancer Development and Progression

作　　者：钱丽媛 李长菲[2,3] 罗云敬 孟颂东[2,3,4] QIAN Li-Yuan;LI Chang-Fei;LUO Yun-Jing;MENG Song-Dong(Beijing Key Laboratory of Environmental and Viral Oncology,Faculty of Environmental and Energy Engineering,Beijing University of Technology,Beijing 100124,China;CAS Key Laboratory of Pathogenic Microbiology and Immunology,Institute of Microbiology,Chinese Academy of Sciences,Beijing 100101,China;University of Chinese Academy of Sciences,Beijing 100049,China;Beijing ComingHealth Bio Tec Co.,LTD,Beijing 100081,China)

机构地区：[1]北京工业大学环境与生命学部,环境与病毒肿瘤学北京市重点实验室,北京100124 [2]中国科学院微生物研究所,中国科学院病原微生物与免疫学重点实验室,北京100101 [3]中国科学院大学,北京100049 [4]北京康明海慧生物科技有限公司,北京100081

出　　处：《生物化学与生物物理进展》2021年第9期993-1005,共13页Progress In Biochemistry and Biophysics

基　　金：国家自然科学基金(81761128002,81621091,81871297,81672815);中国科学院B类先导项目(XDB29040000)资助。

摘　　要：热休克蛋白90B1又称为糖蛋白96(gp96).gp96属于热休克蛋白90家族,是一种高度保守且普遍存在的糖蛋白.作为一种内质网蛋白,gp96在维持内质网稳态、内质网应激、钙稳态等方面起着重要的调控作用,这些调控网络在肿瘤的发生发展过程中起着重要的作用.gp96作为分子伴侣在稳定和激活客户蛋白等方面有众多报道,其中包括HER2、整合素和Toll样受体等多个客户蛋白.大量研究表明,gp96在肝癌、乳腺癌、胃癌等不同类型的肿瘤中高表达,并在肿瘤的生长、侵袭和转移等方面起着重要的作用.本文从gp96的基本结构和功能及其在肿瘤发生发展中的作用等方面进行综述,并着重阐述细胞膜gp96相关的研究进展.最后,重点介绍基于胞膜gp96结构所设计的选择性小分子抑制剂、抗体和多肽等药物在肿瘤靶向治疗中的潜在应用.Glycoprotein 96(gp96)is a highly conserved and ubiquitous glycoprotein that belongs to the heat shock protein 90(HSP90)family.It comprises 4 domains:N-terminal domain(NTD),middle domain(MD),Cterminal domain(CTD)and charged linker region(CR).Each domain performs a specific function.NTD containing the nucleotide binding site interacts with and hydrolyzes ATP.MD is involved in client protein recognition,and is the site of constitutive dimerization.The ATP hydrolytic activity of NTD requires cooperative action of CR and MD.The schematic representation of gp96 topology is shown in the main text.An increased expression of gp96 has been reported in multiple cancers.Its upregulation in tumors is closely correlated with poor prognosis and decreased overall survival of patients,indicating that gp96 serves as a potential diagnostic and prognostic biomarker.As a chaperone protein gp96 directs the folding and/or assembly of secreted and membrane proteins.It has a limited client protein profile that is involved in key processes linked with the hallmarks of cancer.Previous studies have shown that cellular gp96 physically interacts with and directs the folding and assembly of several client proteins,including insulin-like growth factors(IGF),integrins,epidermal growth factor receptor-2(HER2)and Wnt co-receptor LRP6,which are involved in the regulation of cell multiplication,normal tissue differentiation,cancer progression and metastasis.It has been found that gp96 was only expressed on cell surface of malignant tumor but not benign tissues.Cell membrane gp96 is closely associated with cancer cell proliferation,invasion,and metastasis.We further demonstrated that gp96 on cell membrane interacts with HER2,urokinase-type plasminogen activator-receptor(uPAR)or ER-α36.Targeting gp96 by siRNA or a monoclonal antibody for gp96 led to decreased cell growth and invasion,increased apoptosis in vitro,and suppression of tumor growth in vivo,validating cell membrane gp96 as a therapeutic target.At present,the selective smallmolecule inhibit

关 键 词：热休克蛋白GP96 分子伴侣 胞膜gp96 肿瘤 靶向治疗 

分 类 号：K826.15[历史地理—历史学] Q5[生物学—生物化学]