肝细胞癌中趋化因子CXCL10及其受体CXCR3的表达及临床意义分析

张婧; 陈洁; 关贵文; 张婷; 鲁凤民; 陈香梅

doi:10.19723/j.issn.1671-167X.2019.03.005

北京大学学报（医学版） >

2019 , Vol. 51 >Issue 3: 402 - 408

DOI: https://doi.org/10.19723/j.issn.1671-167X.2019.03.005

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肝细胞癌中趋化因子CXCL10及其受体CXCR3的表达及临床意义分析

张婧 ,
陈洁 ,
关贵文 ,
张婷 ,
鲁凤民 ,
陈香梅

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北京大学基础医学院病原生物学系暨北京大学感染病研究中心,北京 100191

鲁凤民,北京大学基础医学院病原生物学系及北京大学感染病研究中心教授、学系主任,博士生导师。长期从事病毒性肝炎、肿瘤等相关研究。主持或参加了国家“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项、国家高技术研究发展计划(863计划)、国家重点基础研究发展计划(973计划)及国家自然科学基金面上项目。担任国务院学位委员会基础医学学组委员、中国医药质量协会转化医学分会主任委员、中国研究型医院分子诊断专业委员会副主任委员、中华医学会医学病毒学分会委员、北京市医学病毒学分会副主任委员、中国微生物学会病毒学工作委员会常委、北京市微生物学会常委等,并担任《中华肝脏病杂志》《中华预防医学杂志》等期刊常务编委或编委。主要学术成就是实验证实了乙型肝炎病毒RNA病毒样颗粒的存在,提出了以血清乙型肝炎病毒RNA的持续消失作为慢性乙肝核苷(酸)类似物抗病毒治疗安全停药和准功能性治愈的概念。在New England Journal of Medicine、Journal of Hepatology、 Cancer Research等SCI杂志发表论文120篇,他引超过3 200次。曾作为参加人两次获得国家科学技术进步奖二等奖。|陈香梅,北京大学基础医学院病原生物学系及北京大学感染病研究中心副教授,博士生导师,主要研究方向为病毒和宿主因素在乙肝疾病进展和肝癌发生中的作用及机制。主要研究工作包括:乙型肝炎病毒整合的致癌新机制、乙型肝炎相关肝癌发生发展的分子机制、影响慢性乙型肝炎疾病进展的宿主遗传易感性等。近五年主持和参加的课题有国家“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项、国家自然科学基金面上项目、北京市自然科学基金面上项目、北京市科委首都市民培育项目等。现任中华医学会肝病学分会青年委员、中华医学会病毒学分会临床病毒学组委员、北京市医学会肝病学会委员、中国医药质量管理协会转化医学分会副主任委员,《中华肝脏病杂志》《微生物学免疫学进展》等杂志编委。作为第一作者或通信作者在Journal of Hepatology、Oncogene、 Liver International等杂志发表SCI论文20余篇,曾获得国家科学技术进步奖二等奖1次(第8完成人)。

收稿日期: 2019-03-25

网络出版日期: 2019-06-26

基金资助

北京市自然科学基金(7182079)

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Expression and clinical significance of chemokine CXCL10 and its receptor CXCR3 in hepatocellular carcinoma

Jing ZHANG ,
Jie CHEN ,
Gui-wen GUAN ,
Ting ZHANG ,
Feng-min LU ,
Xiang-mei CHEN

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Department of Microbiology & Infectious Disease Center, Peking University School of Basic Medical Sciences, Beijing 100191, China

Received date: 2019-03-25

Online published: 2019-06-26

Supported by

Supported by Beijing Natural Science Foundation(7182079)

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摘要

目的探索趋化因子CXCL10及其受体CXCR3基因在肝细胞癌(hepatocellular carcinoma,HCC)中的表达及其临床意义。方法通过挖掘癌症基因组图谱(the cancer genome atlas,TCGA)中HCC数据库和国际肝癌研究所(Liver Cancer Institute,LCI)中乙肝相关肝癌数据库,分析CXCL10基因和CXCR3基因在HCC及癌旁组织中的表达以及与患者术后总生存率的关系;采用实时荧光定量PCR(quantitative real-time PCR,qPCR)方法检测45例乙肝相关HCC患者临床样本中CXCL10基因和CXCR3基因的表达情况,并分析CXCL10和CXCR3基因表达的相关性。结果 TCGA数据库中CXCL10基因在HCC组织中的表达显著高于癌旁组织(非配对样本:3.379±2.081 vs. 2.213±2.274,P<0.001;配对样本:3.159±2.267 vs. 2.213±2.274,P=0.018),LCI数据库中CXCL10基因在HCC组织中的表达显著高于癌旁组织(7.625±1.683 vs. 7.287±1.328,P=0.009),TCGA和LCI数据库中CXCL10基因高表达HCC患者术后总体生存率高于CXCL10基因低表达患者(P=0.107,P=0.002)。TCGA数据库中CXCR3基因在HCC组织的表达显著高于癌旁组织(非配对样本:-0.906±1.697 vs. -1.978±1.629,P<0.001;配对样本:-1.329±1.732 vs. -1.978±1.629,P=0.037),而LCI数据库中CXCR3基因在乙肝相关HCC组织的表达显著低于癌旁组织(3.989±0.339 vs. 4.074±0.309,P=0.003),但两个数据库中HCC组织CXCR3基因高表达患者的术后总体生存率均显著高于CXCR3基因低表达患者(P=0.004,P=0.014)。TCGA数据库中CXCL10基因与CXCR3基因在HCC和癌旁组织里的表达水平均呈正相关(r=0.584,P<0.001;r=0.776,P<0.001)。临床样本检测结果显示,CXCL10基因在乙肝相关HCC和配对癌旁组织里的表达水平分别为0.479(0.223,1.094)和0.484(0.241,0.846),均显著高于正常肝组织的0.131(0.106,0.159)(P=0.010,P<0.001), CXCR3基因在HCC和配对癌旁组织里的表达水平分别为0.011(0.006,0.019)和0.016(0.011,0.021),也显著高于正常肝组织的0.002(0.001,0.004)(P=0.004,P<0.001), 但CXCL10和CXCR3基因在HCC组织中的表达水平与配对癌旁组织相比差异均无统计学意义(P=1.000,P=0.374)。结论 CXCL10在不同病因HCC组织中均呈高表达,CXCR3在乙肝相关HCC组织中呈低表达,HCC组织中CXCL10和CXCR3的高表达均利于HCC患者的术后生存。

关键词： 趋化因子; 趋化因子受体; 肝细胞癌

本文引用格式

张婧 , 陈洁 , 关贵文 , 张婷 , 鲁凤民 , 陈香梅 . 肝细胞癌中趋化因子CXCL10及其受体CXCR3的表达及临床意义分析[J]. 北京大学学报（医学版）, 2019 , 51(3) : 402 -408 . DOI: 10.19723/j.issn.1671-167X.2019.03.005

Abstract

Objective: To explore the expression and clinical significance of chemokine CXCL10 and CXCR3 in hepatocellular carcinoma (HCC).Methods: The expression and prognostic of CXCL10 and CXCR3 in HCC tumor tissues and non-tumor tissues were analyzed in two different publicly available databases the Cancer Genome Atlas (TCGA) and Liver Cancer Institute (LCI). In addition, quantitative real-time PCR (qPCR) was used to detect the mRNA expression of CXCL10 and CXCR3 in 45 HCC cli-nical samples with HBV infection background. Pearson correlation and Spearman rank correlation were used to determine the correlation between the expression level of CXCL10 and CXCR3 in tumor and non-tumor tissues. Results: In TCGA database, the expression of CXCL10 in HCC tumor tissues was significantly higher than that in non-tumor tissues (nonpaired samples: 3.379±2.081 vs. 2.213±2.274, P<0.001; paired samples: 3.159±2.267 vs. 2.213±2.274, P=0.018). Similarly in LCI datebase (7.625±1.683 vs. 7.287±1.328, P=0.009). And higher CXCL10 expression was significantly associated with a better prognosis in the patients with HCC both in TCGA and LCI database (P=0.107, P=0.002). In TCGA database, the expression of CXCR3 in HCC tumor tissues was significantly higher than that in non-tumor tissues (nonpaired samples: -0.906±1.697 vs. -1.978±1.629, P<0.001; paired samples: -1.329±1.732 vs. -1.978±1.629, P=0.037), while lower in LCI database (3.989±0.339 vs. 4.074±0.309, P=0.003). In both databases, higher CXCR3 expression was significantly associated with a better prognosis in the HCC patients (P=0.004, P=0.014). Furthermore, in TCGA database, the expression level of CXCL10 and CXCR3 was positively correlated both in HCC tumor tissues and matched non-tumor tissues (r=0.584, P<0.001; r=0.776, P<0.001). The qPCR assay showed that the expression of CXCL10 in HBV-related HCC tumor tissues was significantly higher than those in normal liver tissues [0.479(0.223, 1.094) vs. 0.131(0.106, 0.159), P=0.010], and the expression in HBV-related non-tumor tissues was also significantly higher than those in normal liver tissues [0.484(0.241, 0.846) vs. 0.131(0.106, 0.159), P<0.001]. The same was true as CXCR3 [0.011(0.006, 0.019) vs. 0.002(0.001, 0.004), P=0.004; 0.016(0.011, 0.021) vs. 0.002(0.001, 0.004), P<0.001]. However there was no significant difference of CXCL10 and CXCR3 between tumor tissues and matched non-tumor tissues (P=1.000, P=0.374).Conclusion: Expression of CXCL10 was up-regulated in HCC tissues, expression of CXCR3 was down-regulated in HBV-related HCC tissues, and the higher expression of both genes was correlated with better overall survival in HCC patients.

Key words： Chemokine; Chemokine receptor; Hepatocellular carcinoma

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