巨噬细胞穹窿主体蛋白重塑免疫微环境抑制肝癌发生发展  

Major Vault Protein in Macrophages Reprograms Immune Microenvironment and Inhibits Occurrence and Development of Liver Cancer

作　　者：周诗萌 李梦梦 王守宇 ZHOU Shimeng;LI Mengmeng;WANG Shouyu(Medical School of Nanjing University,Nanjing 210008,China)

机构地区：[1]南京大学医学院,南京210008

出　　处：《肿瘤防治研究》2025年第2期118-126,共9页Cancer Research on Prevention and Treatment

基　　金：国家自然科学基金(82273157,82073114)。

摘　　要：目的探讨肿瘤相关巨噬细胞中穹窿主体蛋白(MVP)在肝癌发生发展中的作用及分子机制。方法通过生物信息学和多重荧光免疫组织化学染色法分析原发性肝癌组织中巨噬细胞中MVP的表达情况,通过Cre/LoxP重组酶系统构建巨噬细胞MVP特异性敲除小鼠。克隆形成、Transwell迁移实验检测肿瘤细胞增殖、迁移能力;小鼠原发性肝癌、皮下瘤移植模型探究巨噬细胞中MVP对肿瘤发生发展的影响;多重荧光免疫组织化学染色法探究巨噬细胞MVP对肿瘤免疫微环境的影响;细胞共培养、流式细胞术、qPCR、ELISA法检测巨噬细胞中MVP对CD8^(+)T细胞的影响。结果肿瘤相关巨噬细胞中MVP表达丰度较高;与癌旁组织相比,原发性肝癌患者的肿瘤浸润巨噬细胞中MVP表达下调;巨噬细胞MVP缺失促进肿瘤细胞的增殖和迁移(P<0.05)、促进肿瘤发生和生长(P<0.05)、介导肿瘤组织中免疫抑制微环境的形成及减弱CD8+T细胞介导的抗肿瘤免疫(P<0.05)。结论巨噬细胞中MVP缺失抑制CD8+T细胞功能促进肝癌的发生发展。Objective To explore the role and molecular mechanism of major vault protein(MVP)in tumorassociated macrophages in the occurrence and development of liver cancer.Methods The expression of MVP in macrophages was analyzed by bioinformatics method and multi-fluorescent immunohistochemical staining.Mice with MVP deficiency in macrophages were constructed by Cre/LoxP recombinant enzyme system.The proliferation and migration abilities of tumor cells were detected by cloning formation and Transwell migration assays.The effect of MVP in macrophages on tumorigenesis and development was investigated by mouse primary liver cancer model and subcutaneous tumor transplantation model.The effect of MVP on the tumor microenvironment was investigated by multi-fluorescent immunohistochemical staining.The effect of MVP on CD8+T cells was detected by cell co-culture,flow cytometry,qPCR,and ELISA.Results The high expression of MVP in tumor-associated macrophages.The downregulation of the expression of MVP in tumor-associated macrophages compared with para-carcinoma tissues.MVP deficiency in macrophages promoted the proliferation and migration of tumor cells(P<0.05),promoted the development of tumor in vivo(P<0.05),formed an immunosuppressive microenvironment and weakened CD8+T cellmediated anti-tumor immunity(P<0.05).Conclusion MVP deficiency in macrophages can promote the occurrence and development of liver cancer by suppressing the function of CD8^(+)T cells.

关 键 词：穹窿主体蛋白 肝癌 肿瘤微环境 巨噬细胞 CD8^(+)T细胞 

分 类 号：R735.7[医药卫生—肿瘤]