谢宏俊,阙滔滔,魏 毅,等.肾细胞癌PBRM1表达缺失抑制CD8+ T细胞浸润[J].肿瘤学杂志,2022,28(7):579-585.
肾细胞癌PBRM1表达缺失抑制CD8+ T细胞浸润
PBRM1 Deletion Inhibits CD8+ T Cells Infiltration in Tumor Microenvironment of Renal Cell Carcinoma
投稿时间:2022-02-21  
DOI:10.11735/j.issn.1671-170X.2022.07.B009
中文关键词:  肾细胞癌  PBRM1  外泌体  CD8+T细胞  EZH2
英文关键词:renal cell carcinoma  PBRM1  exosome  CD8+T cell  EZH2
基金项目:国家自然科学基金(82072829),陕西省自然科学基础研究计划-面上项目(2021JM-265)
作者单位
谢宏俊 西安交通大学第一附属医院环境和疾病相关基因教育部重点实验室肿瘤研究室陕西省肿瘤精准医学重点实验室 
阙滔滔 西安交通大学第一附属医院环境和疾病相关基因教育部重点实验室肿瘤研究室陕西省肿瘤精准医学重点实验室 
魏 毅 西安交通大学第一附属医院环境和疾病相关基因教育部重点实验室肿瘤研究室陕西省肿瘤精准医学重点实验室 
范义增 西安交通大学第一附属医院环境和疾病相关基因教育部重点实验室肿瘤研究室陕西省肿瘤精准医学重点实验室 
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中文摘要:
      摘 要:[目的] 探讨PBRM1调控CD8+T在肾透明细胞癌组织中细胞浸润的分子机制。[方法] 以肾透明细胞癌患者肿瘤临床标本为研究对象,探讨CD8+T细胞在人肾癌中的浸润及其与临床病理特征的关系,以免疫印迹、荧光免疫、ELISA等分子生物学方法明确PBRM1调控CD8+T细胞浸润的分子机制。免疫荧光检测CD63、EZH2及PHK26在细胞中的分布。免疫印迹检测IFN-γ,IL-6和TNF-α不同因子处理对肾癌细胞EZH2的诱导表达。实验结果经GraphPad Prism软件, t检验对两组间差异进行统计学分析。[结果] 肾透明细胞癌组织免疫组化结果显示,在肿瘤组织中CD8+T细胞浸润数量显著性下降(P<0.001),CD8+T细胞浸润与患者总生存期呈正相关(P<0.001)。患者肿瘤组织PBRM1着色和CD8+T细胞浸润数量结果显示:PBRM1表达与CD8+T细胞浸润数量呈正相关(P<0.001)。IFN-γ,IL-6和TNF-α细胞因子促进EZH2在细胞表达升高,同时被外泌体包载被运输到受体细胞,外泌体EZH2进入受体细胞抑制CXCL9和CXCL10细胞因子分泌。[结论] PBRM1缺失激活exo-EZH2/CXCL9(10)信号轴抑制CD8+T细胞肿瘤组织浸润。
英文摘要:
      Abstract:[Objective] To explore the molecular mechanism of PBRM1 in regulating CD8+T cell infiltration in clear cell renal cell carcinoma tissue. [Methods] The expression of PBRM1 in renal clear cell carcinoma were detected by tissue microarray and its relation with CD8+T cell infiltration in tumor microenvironment was analyzed. Western blot was also applied to detect EZH2 expression after IFN-γ, IL-6 and TNF-α treatment in renal cell carcinoma cells. Immunofluorescence was used to detect the distribution of CD63, EZH2 and PHK26 in cells. The effect of EZH2 on CXCL9/10 secretion was detected by ELISA assay. The GraphPad Prism software was used for statistical analysis. [Results] Tissue microarray results showed that the infiltration density of CD8+T cells in tumor tissues was lower than that in adjacent tissues(P<0.001). High CD8+T cell infiltration was positively correlated with the overall survival of patients(P<0.001), and low PBRM1 protein expression was associated with decreased infiltration of CD8+T cells(P<0.001). IFN-γ, IL-6 and TNF-α promoted the expression of EZH2 protein, which was packaged in exosomes and entered into recipient cells to inhibit CXCL9 and CXCL10 secretion. [Conclusion] PBRM1 deletion activates the exo-EZH2/CXCL9(10) signal axis and inhibits CD8+T cell tumor tissue infiltration in renal cell carcinoma.
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