外泌体微小RNA作为肝细胞肝癌生物标志物的研究进展

doi:10.3969/j.issn.1673-8640.2025.04.002

检验医学 ›› 2025, Vol. 40 ›› Issue (4): 317-323.DOI: 10.3969/j.issn.1673-8640.2025.04.002

• 肝癌新标志物基础研究和临床应用专题 • 上一篇下一篇

外泌体微小RNA作为肝细胞肝癌生物标志物的研究进展

田泽¹, 刘宏瑞², 司文喆¹()

1.北京大学第三医院检验科国家卫生健康委员会心血管分子生物学与调节肽重点实验室，北京 100191
2.北京大学血管稳态与重构全国重点实验室，北京 100191

收稿日期:2024-03-12 修回日期:2024-10-31 出版日期:2025-04-30 发布日期:2025-05-08
通讯作者: 司文喆，E-mail：wenzhesi@bjmu.edu.cn。
作者简介:田泽，男，2004年生，主要从事临床检验工作；刘宏瑞，女，2004年生，主要从事临床检验工作。田泽和刘宏瑞对本研究具有同等贡献，并列为第一作者。
基金资助:
国家自然科学基金面上项目(81972659);国家自然科学基金面上项目(82303063);北京市科学技术委员会科技新星计划(20220484090);北京市自然科学基金项目(7232206);北京市科学技术委员会科技新星计划交叉合作课题(20230484442);北京大学第三医院交叉联合专项资助项目(BYSYJC2024041);北京大学第三医院血管稳态与重构全国重点实验室课题(2024-VHR-SY-13)

Research progress of exosomal miRNA as biomarkers of hepatocellular carcinoma

TIAN Ze¹, LIU Hongrui², SI Wenzhe¹()

1. Department of Clinical Laboratory，Peking University Third Hospital，Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides，National Health Commission，Beijing 100191，China
2. Peking University，State Key Laboratory of Vascular Homeostasis and Remodeling，Beijing 100191，China

Received:2024-03-12 Revised:2024-10-31 Online:2025-04-30 Published:2025-05-08

摘要/Abstract

摘要：

肝细胞肝癌（HCC）是一种常见的原发性消化系统恶性肿瘤，致死率高，因其起病隐匿，早期诊断非常困难，大多数患者在确诊时已处于中晚期，预后较差。传统的血清标志物在HCC诊断中存在敏感性和特异性不足的问题。外泌体作为肿瘤微环境中细胞之间的重要通讯媒介，已逐渐被用于HCC的辅助诊断。外泌体中的微小RNA（miRNA）与HCC的发生、发展密切相关。文章综述了外泌体miRNA在HCC发生、发展中的应用价值，如诊断效能、疗效评估价值、与肝硬化（LC）的鉴别诊断价值，以及外泌体中不同miRNA联合检测在HCC疾病分层和预后评估中的价值；同时，简述了外泌体的提取和外泌体中miRNA的检测方法，以明确外泌体miRNA作为HCC潜在生物标志物的优势和价值，并对未来研究方向作出展望。

关键词: 微小RNA, 外泌体, 肝细胞肝癌

Abstract:

Hepatocellular carcinoma（HCC） is a common primary malignant tumor of the digestive system with a high mortality. Due to its insidious onset，early diagnosis is very challenging，and most of the patients are diagnosed at an advanced stage，resulting in a poor prognosis. Traditional serum biomarkers have limitations in sensitivity and specificity for HCC diagnosis. Exosomes，as important communication mediators within the tumor microenvironment，have gradually been utilized for the auxiliary diagnosis of HCC. MicroRNA（miRNA） within exosomes is related to the occurrence and progression of HCC. This review focuses on the application value of exosomal miRNA in the development and progression of HCC，including diagnostic efficacy，therapeutic evaluation and the role in differentiating HCC from liver cirrhosis（LC）. It also discusses the value of combined determination of different miRNA in exosomes for disease stratification and prognosis assessment in HCC. Additionally，the methods for exosome extraction and miRNA determination are described to highlight the advantages and potential of miRNA as biomarkers for HCC，and future research directions are outlined.

Key words: MicroRNA, Exosome, Hepatocellular carcinoma

中图分类号:

R446.1

田泽, 刘宏瑞, 司文喆. 外泌体微小RNA作为肝细胞肝癌生物标志物的研究进展[J]. 检验医学, 2025, 40(4): 317-323.

TIAN Ze, LIU Hongrui, SI Wenzhe. Research progress of exosomal miRNA as biomarkers of hepatocellular carcinoma[J]. Laboratory Medicine, 2025, 40(4): 317-323.

图/表 2

参考文献 52

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标志物	AUC	样本量	外泌体提取方法	分子机制	参考文献
miR-122↑	0.990	HCC患者50例，正常对照者50例	差速离心法	由坏死肝细胞大量释放	[35]
miR-4661-5p↑	所有分期患者的AUC为0.917，早期患者的AUC为0.923	HCC患者45例（未分化HCC患者18例），LC患者10例，CH患者20例，正常对照者15例	聚合物共沉淀法		[21]
miR-4661-5p↑与miR-4746-5p↑联合检测	0.947
miR-21-5p↑			超滤法和超速离心法	外泌体miR-21-5p通过促进白细胞介素-10的产生促进HCC肿瘤细胞的生长	[37]
AFP与miR-21-5p↑、miR-92a-3p↓联合检测	0.850	HCC患者48例，LC患者38例，正常对照者20例	聚合物共沉淀法和差速离心法	miR-21增加通过激活癌症相关成纤维细胞促进癌症进展，且抑制PTEN的表达，促进HCC细胞的增殖和转移；miR-92a的下调抑制了HCC生长	[22]
miR-21↑		HCC患者30例，正常对照者30例	差速离心法	与肿瘤分期相关	[38]
miR-155↑		HCC患者40例	聚合物共沉淀法	缺氧条件下促进内皮细胞的血管生成	[39]
miR-939↑	0.840	LC患者118例，单灶/小HCC患者40例，中晚期HCC患者47例	差速离心法	miRNA通过肿瘤细胞、免疫系统的细胞和肿瘤周围微环境的细胞被释放到血液中	[40]
miR-595↑	0.920
miR-519d↑	0.820
miR-494↑	0.730
miR-25-3p↑	0.758	正常对照者22例，CH患者20例，LC患者28例，Ⅰ~Ⅱ期HCC患者34例，Ⅲ~Ⅳ期HCC患者36例	ExoQuick		[21]
miR-1269a↑	0.848
miR-4661-5p↑	0.917
miR-4746-5p↑	0.660
miR-23a-5p↓		HCC患者110例	差速离心法	外泌体miR-23a-5p可抑制HCC细胞增殖和血管生成	[41]
miR-26a↓		HCC患者血液样本168例，组织样本267例	超滤法和超速离心法	外泌体miR-26a是HCC的一种抑癌基因miRNA，在HCC组织中低表达	[42]
miR-374c-5p↓		HCC患者60例	离心法	外泌体miR-374c-5p通过LIMK1-Wnt/β-连环蛋白轴靶向抑制EMT，参与TGF-β1诱导的HCC转移	[43]
miR-93↑		HCC患者375例，正常对照者50例	ExoQuick	外泌体miR-93通过抑制其靶基因PTEN的表达来激活Akt通路	[44]
miR-652-3p↑			差速离心法	外泌体miR-652-3p通过靶向TNRC6A促进肝癌细胞的增殖和转移	[45]
miR-3174↑	0.630	HCC患者80例	超速离心法	外泌体miR-3174通过抑制HIPK3来促进HCC的血管生成和转移	[46]

标志物	AUC	样本量	外泌体提取方法	分子机制	参考文献
miR-122↑	0.990	HCC患者50例，正常对照者50例	差速离心法	由坏死肝细胞大量释放	[35]
miR-4661-5p↑	所有分期患者的AUC为0.917，早期患者的AUC为0.923	HCC患者45例（未分化HCC患者18例），LC患者10例，CH患者20例，正常对照者15例	聚合物共沉淀法		[21]
miR-4661-5p↑与miR-4746-5p↑联合检测	0.947
miR-21-5p↑			超滤法和超速离心法	外泌体miR-21-5p通过促进白细胞介素-10的产生促进HCC肿瘤细胞的生长	[37]
AFP与miR-21-5p↑、miR-92a-3p↓联合检测	0.850	HCC患者48例，LC患者38例，正常对照者20例	聚合物共沉淀法和差速离心法	miR-21增加通过激活癌症相关成纤维细胞促进癌症进展，且抑制PTEN的表达，促进HCC细胞的增殖和转移；miR-92a的下调抑制了HCC生长	[22]
miR-21↑		HCC患者30例，正常对照者30例	差速离心法	与肿瘤分期相关	[38]
miR-155↑		HCC患者40例	聚合物共沉淀法	缺氧条件下促进内皮细胞的血管生成	[39]
miR-939↑	0.840	LC患者118例，单灶/小HCC患者40例，中晚期HCC患者47例	差速离心法	miRNA通过肿瘤细胞、免疫系统的细胞和肿瘤周围微环境的细胞被释放到血液中	[40]
miR-595↑	0.920
miR-519d↑	0.820
miR-494↑	0.730
miR-25-3p↑	0.758	正常对照者22例，CH患者20例，LC患者28例，Ⅰ~Ⅱ期HCC患者34例，Ⅲ~Ⅳ期HCC患者36例	ExoQuick		[21]
miR-1269a↑	0.848
miR-4661-5p↑	0.917
miR-4746-5p↑	0.660
miR-23a-5p↓		HCC患者110例	差速离心法	外泌体miR-23a-5p可抑制HCC细胞增殖和血管生成	[41]
miR-26a↓		HCC患者血液样本168例，组织样本267例	超滤法和超速离心法	外泌体miR-26a是HCC的一种抑癌基因miRNA，在HCC组织中低表达	[42]
miR-374c-5p↓		HCC患者60例	离心法	外泌体miR-374c-5p通过LIMK1-Wnt/β-连环蛋白轴靶向抑制EMT，参与TGF-β1诱导的HCC转移	[43]
miR-93↑		HCC患者375例，正常对照者50例	ExoQuick	外泌体miR-93通过抑制其靶基因PTEN的表达来激活Akt通路	[44]
miR-652-3p↑			差速离心法	外泌体miR-652-3p通过靶向TNRC6A促进肝癌细胞的增殖和转移	[45]
miR-3174↑	0.630	HCC患者80例	超速离心法	外泌体miR-3174通过抑制HIPK3来促进HCC的血管生成和转移	[46]

外泌体微小RNA作为肝细胞肝癌生物标志物的研究进展

Research progress of exosomal miRNA as biomarkers of hepatocellular carcinoma

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[3]	王晓龙, 陈元斌. 血清CDC42与AFP阴性HCC患者临床病理特征和预后的相关性[J]. 检验医学, 2025, 40(3): 259-263.
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[6]	王榕, 高春芳. 外泌体糖基化在肿瘤诊断和治疗中的应用进展[J]. 检验医学, 2024, 39(4): 404-409.
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[9]	刘俊汝, 李萌, 徐阳, 郑伟英. 尿外泌体miR-27a、miR-27b、miR-29c、miR-200c在早期糖尿病肾病诊断中的价值[J]. 检验医学, 2024, 39(11): 1053-1059.
[10]	刘建星, 王金鹏, 耿新龙, 王珊. 尿液外泌体miR-214表达在透明细胞肾细胞癌诊断和预后评估中的价值[J]. 检验医学, 2024, 39(10): 969-974.
[11]	张世球, 吕婕, 俞容, 王川玲, 林子艳, 朱永俊. 基于GEO数据库筛选慢性肾脏病相关差异表达基因及其初步验证[J]. 检验医学, 2024, 39(10): 975-984.
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[14]	王蓉, 邢连翔, 黄克亮, 李欣. miR-374靶向下调TRIM35表达可促进乳腺癌细胞增殖和侵袭[J]. 检验医学, 2023, 38(9): 812-817.
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