检验医学 ›› 2025, Vol. 40 ›› Issue (4): 309-316.DOI: 10.3969/j.issn.1673-8640.2025.04.001
• 肝癌新标志物基础研究和临床应用专题 • 下一篇
收稿日期:
2025-02-17
修回日期:
2025-03-28
出版日期:
2025-04-30
发布日期:
2025-05-08
通讯作者:
卢仁泉,E-mail:作者简介:
马晓路,男,1989年生,博士,技师,主要从事肿瘤分子诊断研究。
基金资助:
MA Xiaolu, GUO Lin, LU Renquan()
Received:
2025-02-17
Revised:
2025-03-28
Online:
2025-04-30
Published:
2025-05-08
摘要:
原发性肝癌是发病率和死亡率均排名前列的恶性肿瘤,肝细胞肝癌(HCC)是其最主要的病理类型。外周血标志物对于HCC的诊断、病情监测和预后评估均有重要作用。目前,临床最常用的HCC外周血标志物是甲胎蛋白(AFP),但仅有50%~60%的HCC患者AFP呈阳性,这极大地限制了AFP的临床应用。近年来,随着各种检测技术的发展,越来越多的新型HCC外周血标志物被发现,如各类蛋白、循环肿瘤DNA(ctDNA)、循环游离RNA、胞外囊泡(EV)、循环肿瘤细胞(CTC),为HCC的精准诊断、预后评估和疗效评估提供了有价值的参考依据。然而,大部分新型标志物的临床意义缺乏系统性回顾,尚未用于临床实践。文章针对HCC外周血指标的临床价值进行回顾,并对其应用前景进行述评。
中图分类号:
马晓路, 郭林, 卢仁泉. 原发性肝细胞肝癌患者外周血指标的临床价值及其应用前景[J]. 检验医学, 2025, 40(4): 309-316.
MA Xiaolu, GUO Lin, LU Renquan. Clinical value and application prospect of circulating biomarkers in hepatocellular carcinoma patients[J]. Laboratory Medicine, 2025, 40(4): 309-316.
[1] | KIM D Y, TOAN B N, TAN C K, et al. Utility of combining PIVKA-Ⅱ and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region[J]. Clin Mol Hepatol, 2023, 29(2):277-292. |
[2] |
CHOI J G, KIM G A, HAN S B, et al. Longitudinal assessment of three serum biomarkers to detect very early-stage hepatocellular carcinoma[J]. Hepatology, 2019, 69(5):1983-1994.
DOI PMID |
[3] | CHEN J G, PARKIN D M, CHEN Q G, et al. Screening for liver cancer:results of a randomised controlled trial in Qidong,China[J]. J Med Screen, 2003, 10(4):204-209. |
[4] | ZHANG B H, YANG B H, TANG Z Y. Randomized controlled trial of screening for hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2004, 130(7):417-422. |
[5] | ATTIA A M, REZAEE-ZAVAREH M S, HWANG S Y, et al. Novel biomarkers for early detection of hepatocellular carcinoma[J]. Diagnostics(Basel), 2024, 14(20):2278. |
[6] | TIAN B W, YAN L J, DING Z N, et al. Early alpha-fetoprotein response predicts prognosis of immune checkpoint inhibitor and targeted therapy for hepatocellular carcinoma:a systematic review with meta-analysis[J]. Expert Rev Gastroenterol Hepatol, 2023, 17(1):73-83. |
[7] |
ODA K, IDO A, TAMAI T, et al. Highly sensitive lens culinaris agglutinin-reactive α-fetoprotein is useful for early detection of hepatocellular carcinoma in patients with chronic liver disease[J]. Oncol Rep, 2011, 26(5):1227-1233.
DOI PMID |
[8] |
KAGEBAYASHI C, YAMAGUCHI I, AKINAGA A, et al. Automated immunoassay system for AFP-L3% using on-chip electrokinetic reaction and separation by affinity electrophoresis[J]. Anal Biochem, 2009, 388(2):306-311.
DOI PMID |
[9] | ZHANG Y S, CHU J H, CUI S X, et al. Des-γ-carboxy prothrombin(DCP)as a potential autologous growth factor for the development of hepatocellular carcinoma[J]. Cell Physiol Biochem, 2014, 34(3):903-915. |
[10] | XING H, ZHENG Y J, HAN J, et al. Protein induced by vitamin K absence or antagonist-Ⅱ versus alpha-fetoprotein in the diagnosis of hepatocellular carcinoma:a systematic review with meta-analysis[J]. Hepatobiliary Pancreat Dis Int, 2018, 17(6):487-495. |
[11] | KAMEL M M, SAAD M F, MAHMOUD A A, et al. Evaluation of serum PIVKA-Ⅱ and MIF as diagnostic markers for HCV/HBV induced hepatocellular carcinoma[J]. Microb Pathog, 2014, 77:31-35. |
[12] | POTE N, CAUCHY F, ALBUQUERQUE M, et al. Performance of PIVKA-Ⅱ for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion[J]. J Hepatol, 2015, 62(4):848-854. |
[13] | SU T H, WU C H, LIU T H, et al. Clinical practice guidelines and real-life practice in hepatocellular carcinoma:a Taiwan perspective[J]. Clin Mol Hepatol, 2023, 29(2):230-241. |
[14] | TEHRANI H A, ZANGI M, FATHI M, et al. GPC-3 in hepatocellular carcinoma;A novel biomarker and molecular target[J]. Exp Cell Res, 2025, 444(2):114391. |
[15] |
HIPPO Y, WATANABE K, WATANABE A, et al. Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma[J]. Cancer Res, 2004, 64(7):2418-2423.
PMID |
[16] | COUZINET A, SUZUKI T, NAKATSURA T. Progress and challenges in glypican-3 targeting for hepatocellular carcinoma therapy[J]. Expert Opin Ther Targets, 2024, 28(10):895-909. |
[17] | TANGKIJVANICH P, CHANMEE T, KOMTONG S, et al. Diagnostic role of serum glypican-3 in differentiating hepatocellular carcinoma from non-malignant chronic liver disease and other liver cancers[J]. J Gastroenterol Hepatol, 2010, 25(1):129-137. |
[18] | DEVAN A R, NAIR B, PRADEEP G K, et al. The role of glypican-3 in hepatocellular carcinoma:insights into diagnosis and therapeutic potential[J]. Eur J Med Res, 2024, 29(1):490. |
[19] | 汤笑禹, 王砚春, 卢仁泉, 等. 血清GPC3水平在原发性肝细胞癌患者辅助诊断中的应用价值[J]. 中华预防医学杂志, 2020, 54(9):998-1002. |
[20] | 张沛茹, 马晓路, 郭林, 等. 血清GPC3水平在原发性肝细胞肝癌复发预测中的应用价值[J]. 中华预防医学杂志, 2023, 57(6):885-890. |
[21] | JIANG D, ZHANG Y, WANG Y, et al. Diagnostic accuracy and prognostic significance of glypican-3 in hepatocellular carcinoma:a systematic review and meta-analysis[J]. Front Oncol, 2022, 12:1012418. |
[22] | DAI M, CHEN X, LIU X, et al. Diagnostic value of the combination of Golgi protein 73 and alpha-fetoprotein in hepatocellular carcinoma:a meta-analysis[J]. PLoS One, 2015, 10(10):e0140067. |
[23] | SHEN Q, FAN J, YANG X R, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma:a large-scale,multicentre study[J]. Lancet Oncol, 2012, 13(8):817-826. |
[24] | KIYOKAWA H, YASUDA H, OIKAWA R, et al. Serum monomeric laminin-γ2 as a novel biomarker for hepatocellular carcinoma[J]. Cancer Sci, 2017, 108(7):1432-1439. |
[25] | ZENG C, STROUP E K, ZHANG Z, et al. Towards precision medicine:advances in 5-hydroxymethylcytosine cancer biomarker discovery in liquid biopsy[J]. Cancer Commun(Lond), 2019, 39(1):12. |
[26] | KIRK G D, LESI O A, MENDY M, et al. 249(ser)TP53 mutation in plasma DNA,hepatitis B viral infection,and risk of hepatocellular carcinoma[J]. Oncogene, 2005, 24(38):5858-5867. |
[27] |
ZHANG W L, HE H, ZANG M Y, et al. Genetic features of aflatoxin-associated hepatocellular carcinoma[J]. Gastroenterology, 2017, 153(1):249-262.
DOI PMID |
[28] | BARDOL T, PAGEAUX G P, ASSENAT E, et al. Circulating tumor DNA clinical applications in hepatocellular carcinoma:current trends and future perspectives[J]. Clin Chem, 2024, 70(1):33-48. |
[29] | ZHANG Y J, WU C H, SHEN J, et al. Predicting hepatocellular carcinoma by detection of aberrant promoter methylation in serum DNA[J]. Clin Cancer Res, 2007, 13(8):2378-2384. |
[30] |
SHI X W, SHI B H, LYU A L, et al. Exploring genome-wide DNA methylation profiles altered in kashin-beck disease using infinium human methylation 450 bead chips[J]. Biomed Environ Sci, 2016, 29(7):539-543.
DOI PMID |
[31] |
WEN L, LI J Y, GUO H H, et al. Genome-scale detection of hypermethylated CpG islands in circulating cell-free DNA of hepatocellular carcinoma patients[J]. Cell Res, 2015, 25(11):1250-1264.
DOI PMID |
[32] | ZHAO Y T, ZHAO L, JIN H F, et al. Plasma methylated GNB4 and Riplet as a novel dual-marker panel for the detection of hepatocellular carcinoma[J]. Epigenetics, 2024, 19(1):2299044. |
[33] | XU R H, WEI W, KRAWCZYK M, et al. Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma[J]. Nat Mater, 2017, 16(11):1155-1161. |
[34] | KIM D Y, CHO E H, KIN J S, et al. Plasma circulating cell-free DNA in advanced hepatocellular carcinoma patients treated with radiation therapy[J]. In Vivo, 2023, 37(5):2306-2313. |
[35] |
LI W S, ZHANG X, LU X Y, et al. 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers[J]. Cell Res, 2017, 27(10):1243-1257.
DOI PMID |
[36] |
LI X, LIU Y, SALZ T, et al. Whole-genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver[J]. Genome Res, 2016, 26(12):1730-1741.
PMID |
[37] |
CAI J B, CHEN L, ZHANG Z, et al. Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma[J]. Gut, 2019, 68(12):2195-2205.
DOI PMID |
[38] | SONG C X, YIN S L, MA L, et al. 5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages[J]. Cell Res, 2017, 27(10):1231-1242. |
[39] | NING C, CAI P, LIU X, et al. A comprehensive evaluation of full-spectrum cell-free RNAs highlights cell-free RNA fragments for early-stage hepatocellular carcinoma detection[J]. EBioMedicine, 2023, 93:104645. |
[40] | BAI J, JIANG P, JI L, et al. Histone modifications of circulating nucleosomes are associated with changes in cell-free DNA fragmentation patterns[J]. Proc Natl Acad Sci U S A, 2024, 121(42):e2404058121. |
[41] |
AN Y Y, ZHAO X, ZHANG Z T, et al. DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation[J]. Nat Commun, 2023, 14(1):287.
DOI PMID |
[42] |
DENG Z Z, JI Y K, HAN B, et al. Early detection of hepatocellular carcinoma via no end-repair enzymatic methylation sequencing of cell-free DNA and pre-trained neural network[J]. Genome Med, 2023, 15(1):93.
DOI PMID |
[43] | CHENG L, SHARPLES R A, SCICLUNA B J, et al. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood[J]. J Extracell Vesicles, 2014, 3:23743. |
[44] |
ZHOU J, YU L, GAO X, et al. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma[J]. J Clin Oncol, 2011, 29(36):4781-4788.
DOI PMID |
[45] | BI W, LI X, JIANG Y, et al. Tumor-derived exosomes induce neutrophil infiltration and reprogramming to promote T-cell exhaustion in hepatocellular carcinoma[J]. Theranostics, 2025, 15(7):2852-2869. |
[46] |
JIN Y, WONG Y S, GOH B K P, et al. Circulating microRNAs as potential diagnostic and prognostic biomarkers in hepatocellular carcinoma[J]. Sci Rep, 2019, 9(1):10464.
DOI PMID |
[47] | SHAATH H, VISHNUBALAJI R, ELANGO R, et al. Long non-coding RNA and RNA-binding protein interactions in cancer:experimental and machine learning approaches[J]. Semin Cancer Biol, 2022, 86(Pt 3):325-345. |
[48] | ISMAIL M, FADUL M M, TAHA R, et al. Dynamic role of exosomal long non-coding RNA in liver diseases:pathogenesis and diagnostic aspects[J]. Hepatol Int, 2024, 18(6):1715-1730. |
[49] |
XU X Y, GU J M, DING X G, et al. LINC00978 promotes the progression of hepatocellular carcinoma by regulating EZH2-mediated silencing of p21 and E-cadherin expression[J]. Cell Death Dis, 2019, 10(10):752.
DOI PMID |
[50] |
ZENG B, LIN Z W, YE H L, et al. Upregulation of LncDQ is associated with poor prognosis and promotes tumor progression via epigenetic regulation of the EMT pathway in HCC[J]. Cell Physiol Biochem, 2018, 46(3):1122-1133.
DOI PMID |
[51] |
KAMEL M M, MATBOLI M, SALLAM M, et al. Investigation of long noncoding RNAs expression profile as potential serum biomarkers in patients with hepatocellular carcinoma[J]. Transl Res, 2016, 168:134-145.
DOI PMID |
[52] | BADOWSKI C, HE B, GARMIRE L X. Blood-derived lncRNAs as biomarkers for cancer diagnosis:the good,the bad and the beauty[J]. NPJ Precis Oncol, 2022, 6(1):40. |
[53] | ZHANG W, WU W, MENG Q, et al. Research progress on long noncoding RNAs and n6-methyladenosine in hepatocellular carcinoma[J]. Front Oncol, 2022, 12:907399. |
[54] |
TAN W, XIAO C, MA M, et al. Role of non-coding RNA in lineage plasticity of prostate cancer[J]. Cancer Gene Ther, 2025, 32(1):1-10.
DOI PMID |
[55] |
ZHANG X, XU Y F, QIAN Z J, et al. CircRNA_104075 stimulates YAP-dependent tumorigenesis through the regulation of HNF4a and may serve as a diagnostic marker in hepatocellular carcinoma[J]. Cell Death Dis, 2018, 9(11):1091.
DOI PMID |
[56] |
LI Z, ZHOU Y, YANG G, et al. Using circular RNA SMARCA5 as a potential novel biomarker for hepatocellular carcinoma[J]. Clin Chim Acta, 2019, 492:37-44.
DOI PMID |
[57] | YU J, DING W B, WANG M C, et al. Plasma circular RNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma:a large-scale,multicenter study[J]. Int J Cancer, 2020, 146(6):1754-1763. |
[58] | ZHANG Y, YANG X, ZHUANG Z, et al. The diagnostic value of exosomal circular RNAs in cancer patients:a systematic review and meta-analysis[J]. Cancer Med, 2023, 12(2):1709-1720. |
[59] | WELSH J A, GOBERDHAN D C I, O'DRISCOLL L, et al. Minimal information for studies of extracellular vesicles(MISEV2023):from basic to advanced approaches[J]. J Extracell Vesicles, 2024, 13(2):e12404. |
[60] | CHENG L, ZHANG L M, WANG X X, et al. Extracellular vesicles in the HCC microenvironment:implications for therapy and biomarkers[J]. Pharmacol Res, 2024, 209:107419. |
[61] | WANG H, HOU L, LI A, et al. Expression of serum exosomal microRNA-21 in human hepatocellular carcinoma[J]. Biomed Res Int, 2014, 2014:864894. |
[62] | FERRO A, SACCU G, MATTIVI S, et al. Extracellular vesicles as delivery vehicles for non-coding RNAs:potential biomarkers for chronic liver diseases[J]. Biomolecules, 2024, 14(3):277. |
[63] |
SUN N, LEE Y T, ZHANG R Y, et al. Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring[J]. Nat Commun, 2020, 11(1):4489.
DOI PMID |
[64] | KIM S S, BAEK G O, AHN H R, et al. Serum small extracellular vesicle-derived LINC00853 as a novel diagnostic marker for early hepatocellular carcinoma[J]. Mol Oncol, 2020, 14(10):2646-2659. |
[65] | SUN N, ZHANG C, LEE Y T, et al. HCC EV ECG score:an extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma[J]. Hepatology, 2023, 77(3):774-788. |
[66] |
QU Z, WU J H, WU J Y, et al. Exosomal miR-665 as a novel minimally invasive biomarker for hepatocellular carcinoma diagnosis and prognosis[J]. Oncotarget, 2017, 8(46):80666-80678.
DOI PMID |
[67] |
SHI M, JIANG Y, YANG L, et al. Decreased levels of serum exosomal miR-638 predict poor prognosis in hepatocellular carcinoma[J]. J Cell Biochem, 2018, 119(6):4711-4716.
DOI PMID |
[68] |
LEE Y R, KIM G, TAK W Y, et al. Circulating exosomal noncoding RNAs as prognostic biomarkers in human hepatocellular carcinoma[J]. Int J Cancer, 2019, 144(6):1444-1452.
DOI PMID |
[69] |
WANG G Y, LIU W, ZOU Y, et al. Three isoforms of exosomal circPTGR1 promote hepatocellular carcinoma metastasis via the miR449a-MET pathway[J]. EBioMedicine, 2019, 40:432-445.
DOI PMID |
[70] | ZHANG P F, GAO C, HUANG X Y, et al. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma[J]. Mol Cancer, 2020, 19(1):110. |
[71] | CHAN Y T, ZHANG C, WU J, et al. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma[J]. Mol Cancer, 2024, 23(1):189. |
[72] |
WENT P T, LUGLI A, MEIER S, et al. Frequent EpCam protein expression in human carcinomas[J]. Hum Pathol, 2004, 35(1):122-128.
DOI PMID |
[73] |
ZHU L, LIN H B, WAN S, et al. Efficient isolation and phenotypic profiling of circulating hepatocellular carcinoma cells via a combinatorial-antibody-functionalized microfluidic synergetic-chip[J]. Anal Chem, 2020, 92(22):15229-15235.
DOI PMID |
[74] |
WANG Z, LUO L, CHENG Y, et al. Correlation between postoperative early recurrence of hepatocellular carcinoma and mesenchymal circulating tumor cells in peripheral blood[J]. J Gastrointest Surg, 2018, 22(4):633-639.
DOI PMID |
[75] | GUO W, SUN Y F, SHEN M N, et al. Circulating tumor cells with stem-like phenotypes for diagnosis,prognosis,and therapeutic response evaluation in hepatocellular carcinoma[J]. Clin Cancer Res, 2018, 24(9):2203-2213. |
[76] | YU J J, LI Y N, SHU C, et al. Prognostic value of preoperative circulating tumor cells for hepatocellular carcinoma with portal vein tumor thrombosis:a propensity score analysis[J]. J Cancer Res Clin Oncol, 2023, 149(11):8981-8991. |
[77] | LEE Y T, SUN N, KIN M Y, et al. Circulating tumor cell-based messenger RNA scoring system for prognostication of hepatocellular carcinoma:translating tissue-based messenger RNA profiling into a noninvasive setting[J]. Liver Transpl, 2022, 28(2):200-214. |
[78] | DOMINGUEZ D A, WONG P, MELSTROM L G. Existing and emerging biomarkers in hepatocellular carcinoma:relevance in staging,determination of minimal residual disease,and monitoring treatment response:a narrative review[J]. Hepatobiliary Surg Nutr, 2024, 13(1):39-55. |
[1] | 李博, 夏永泉, 沈萍, 夏茂, 曾佳威. 肿瘤相关血栓的发生机制[J]. 检验医学, 2025, 40(2): 192-196. |
[2] | 胡刘平, 李月, 成斌, 韦宝生, 蔡建雷, 杜玉珍. 原发性肝癌经放疗和靶向治疗后继发急性早幼粒细胞白血病1例报道并文献复习[J]. 检验医学, 2024, 39(5): 510-512. |
[3] | 周韵斓, 沈立松. 液体活检标志物在非小细胞肺癌中的临床应用和挑战[J]. 检验医学, 2023, 38(9): 807-811. |
[4] | 高锋. 新型肿瘤标志物的临床应用——前景与挑战[J]. 检验医学, 2023, 38(4): 303-306. |
[5] | 吴炯, 胡嘉华, 施美芳, 刘涛, 戴洁, 卢忻怡, 邹政. 前列腺癌生物标志物研究进展[J]. 检验医学, 2023, 38(2): 190-195. |
[6] | 陈馨宁, 黄斐, 姜惠琴, 沈敏娜, 潘柏申, 王蓓丽, 郭玮. 非小细胞肺癌患者血浆EGFR基因c.2572_2573delinsAG位点突变1例报道[J]. 检验医学, 2023, 38(10): 1003-1005. |
[7] | 王芮, 李朝燕, 赵爱光. 循环肿瘤DNA检测在胃癌诊疗中的应用现状[J]. 检验医学, 2022, 37(9): 877-881. |
[8] | 柳行强, 宁立芬, 李琳, 陈忠成. FR+-CTC、ANXA2、ProGRP与肺癌临床病理特征的相关性[J]. 检验医学, 2022, 37(8): 735-740. |
[9] | 吴苏君, 冀恒涛, 彭梦乐. IL-18、IL-37、NLRP3及NK/DC比值在乙型肝炎相关肝硬化中的临床价值[J]. 检验医学, 2022, 37(6): 518-523. |
[10] | 俞琦, 孙懿, 王琼丽, 蔡逸婷, 李莉. 外周血循环肿瘤细胞形态学分析技术在临床检验中的应用[J]. 检验医学, 2022, 37(3): 264-269. |
[11] | 沈素雅, 黄建钊, 李小怀. 循环肿瘤细胞富集技术研究进展[J]. 检验医学, 2022, 37(1): 91-96. |
[12] | 杨朝美, 冯杰, 郎磊, 颜光涛. CTC、CEA、CA125联合检测在结直肠癌中的临床价值[J]. 检验医学, 2021, 36(9): 901-905. |
[13] | 房永贇, 卢大儒, 沈立松. 循环KRAS突变检测在结直肠癌患者新辅助治疗疗效中的临床价值探讨[J]. 检验医学, 2020, 35(9): 875-880. |
[14] | 陈馨宁, 邬升超, 郭玮, 王蓓丽. 血浆ctDNA检测在结直肠癌诊疗中的应用[J]. 检验医学, 2020, 35(9): 948-951. |
[15] | 师越, 董冬. 循环肿瘤DNA在肾细胞癌中的应用研究进展[J]. 检验医学, 2020, 35(9): 952-956. |
阅读次数 | ||||||
全文 |
|
|||||
摘要 |
|
|||||