肿瘤标志物在肝细胞癌诊断及预后中的应用

doi:10.3760/cma.j.cn371439-20220309-00071

摘要/Abstract

摘要：

肿瘤标志物具有无创性、可重复分析、实时监测等特征,其在肝细胞癌早期诊断及预后监测中具有重要的应用价值。近几年,肝细胞癌肿瘤标志物研究发展迅速,既有传统的血清学肿瘤标志物（如甲胎蛋白、异常凝血酶原、高尔基体糖蛋白73、磷脂酰肌醇蛋白聚糖3等）,又有新型的“液体活检”肿瘤标志物（如循环肿瘤细胞、循环肿瘤DNA等）。进一步研究肿瘤标志物与肝细胞癌之间的相关性,可为肝细胞癌治疗及预后评估提供参考。

关键词: 癌,肝细胞, 早期诊断, 预后, 肿瘤标志物

Abstract:

Tumor biomarkers have multiple characteristics, including noninvasive, repeatable analysis and real-time monitoring, and they have important application value in early diagnosis and prognosis monitoring of hepatocellular carcinoma （HCC）. In recent years, the researches on tumor markers of HCC have developed rapidly. There are not only traditional serological tumor markers, such as alpha fetoprotein, des-gamma carboxy prothrombin, Golgi protein 73, glypican-3, etc., but also new emerging "liquid biopsy" tumor markers, such as circulating tumor cells, circulating tumor DNA etc. Further study on the correlation between tumor biomarkers and HCC can provide reference for the treatment and prognosis evaluation of HCC.

Key words: Carcinoma, hepatocellular, Early diagnosis, Prognosis, Tumor biomarker

刘晓婷, 刘洋, 张换勤, 邢金良, 权志博. 肿瘤标志物在肝细胞癌诊断及预后中的应用[J]. 国际肿瘤学杂志, 2022, 49(6): 371-375.

Liu Xiaoting, Liu Yang, Zhang Huanqin, Xing Jinliang, Quan Zhibo. Application of tumor biomarkers in the diagnosis and prognosis of hepatocellular carcinoma[J]. Journal of International Oncology, 2022, 49(6): 371-375.

参考文献 39

[1]	中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版)[J]. 中华肝脏病杂志, 2020, 28(2): 112-128. DOI: 10.3760/cma.j.issn.1007-3418.2020.02.004. doi: 10.3760/cma.j.issn.1007-3418.2020.02.004
[2]	Forner A, Reig M, Bruix J. Hepatocellular carcinoma[J]. Lancet, 2018, 391(10127): 1301-1314. DOI: 10.1016/S0140-6736(18)30010-2. doi: 10.1016/S0140-6736(18)30010-2
[3]	Foerster F, Galle PR. comparison of the current international guidelines on the management of HCC[J]. JHEP Rep, 2019, 1(2): 114-119. DOI: 10.1016/j.jhepr.2019.04.005. doi: 10.1016/j.jhepr.2019.04.005
[4]	Galle PR, Foerster F, Kudo M, et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma[J]. Liver Int, 2019, 39(12): 2214-2229. DOI: 10.1111/liv.14223. doi: 10.1111/liv.14223
[5]	Edoo MIA, Chutturghoon VK, Wusu-Ansah GK, et al. Serum biomarkers AFP, CEA and CA19-9 combined detection for early diagnosis of hepatocellular carcinoma[J]. Iran J Public Health, 2019, 48(2): 314-322.
[6]	Peng C, Ye Y, Wang Z, et al. Circulating microRNAs for the diagnosis of hepatocellular carcinoma[J]. Dig Liver Dis, 2019, 51(5): 621-631. DOI: 10.1016/j.dld.2018.12.011. doi: 10.1016/j.dld.2018.12.011
[7]	Lin K, Huang Q, Zeng J, et al. Clinical significance of alpha-fetoprotein in alpha-fetoprotein negative hepatocellular carcinoma underwent curative resection[J]. Dig Dis Sci, 2021, 66(12): 4545-4556. DOI: 10.1007/s10620-020-06797-z. doi: 10.1007/s10620-020-06797-z
[8]	Tschuor C, Ferrarese A, Kuemmerli C, et al. Allocation of liver grafts worldwide—is there a best system?[J]. J Hepatol, 2019, 71(4): 707-718. DOI: 10.1016/j.jhep.2019.05.025. doi: 10.1016/j.jhep.2019.05.025
[9]	Kim HI, Lim J, Shim JH. Role of the alpha-fetoprotein response in immune checkpoint inhibitor-based treatment of patients with hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2021. Inpress. DOI: 10.1007/s00432-021-03727-y. doi: 10.1007/s00432-021-03727-y
[10]	Ibrahim HM, Elghannam MZ, Elkhawaga OAY, et al. Evaluation of serum alpha fetoprotein-L3 as an accuracy novel biomarker for the early diagnosis of hepatocellular carcinoma in Egyptian patients[J]. Saudi J Biol Sci, 2021, 28(10): 5760-5764. DOI: 10.1016/j.sjbs.2021.06.020. doi: 10.1016/j.sjbs.2021.06.020
[11]	Liu Z, Wu M, Lin D, et al. Des-gamma-carboxyprothrombin is a favorable biomarker for the early diagnosis of alfa-fetoprotein-negative hepatitis B virus-related hepatocellular carcinoma[J]. J Int Med Res, 2020, 48(2): 300060520902575. DOI: 10.1177/0300060520902575. doi: 10.1177/0300060520902575
[12]	Wang X, Zhang W, Liu Y, et al. Diagnostic value of prothrombin induced by the absence of vitamin K or antagonist-Ⅱ (PIVKA-Ⅱ) for early stage HBV related hepatocellular carcinoma[J]. Infect Agent Cancer, 2017, 12: 47. DOI: 10.1186/s13027-017-0153-6. doi: 10.1186/s13027-017-0153-6
[13]	Luo P, Wu S, Yu Y, et al. Current status and perspective biomarkers in AFP negative HCC: towards screening for and diagnosing hepatocellular carcinoma at an earlier stage[J]. Pathol Oncol Res, 2020, 26(2): 599-603. DOI: 10.1007/s12253-019-00585-5. doi: 10.1007/s12253-019-00585-5
[14]	Song T, Wang L, Su B, et al. Diagnostic value of alpha-fetoprotein, Lens culinaris agglutinin-reactive alpha-fetoprotein, and des-gamma-carboxyprothrombin in hepatitis B virus-related hepatocellular carcinoma[J]. J Int Med Res, 2020, 48(3): 300060519889270. DOI: 10.1177/0300060519889270. doi: 10.1177/0300060519889270
[15]	Gatselis NK, Tornai T, Shums Z, et al. Golgi protein-73: a biomarker for assessing cirrhosis and prognosis of liver disease patients[J]. World J Gastroenterol, 2020, 26(34): 5130-5145. DOI: 10.3748/wjg.v26.i34.5130. doi: 10.3748/wjg.v26.i34.5130
[16]	Zhang J, Zhang M, Ma H, et al. A meta-analysis of the prognostic significance of Golgi protein 73 in hepatocellular carcinoma in Chinese patients[J]. Arch Med Sci, 2020, 16(5): 1104-1110. DOI: 10.5114/aoms.2019.83821. doi: 10.5114/aoms.2019.83821 pmid: 32863999
[17]	Ke MY, Wu XN, Zhang Y, et al. Serum GP 73 predicts posthepatectomy outcomes in patients with hepatocellular carcinoma[J]. J Transl Med, 2019, 17(1): 140. DOI: 10.1186/s12967-019-1889-0. doi: 10.1186/s12967-019-1889-0
[18]	Gao J, Song P. combination of triple biomarkers AFP, AFP-L3, and PIVAKⅡ for early detection of hepatocellular carcinoma in China: expectation[J]. Drug Discov Ther, 2017, 11(3): 168-169. DOI: 10.5582/ddt.2017.01036. doi: 10.5582/ddt.2017.01036
[19]	Liu D, Luo Y, Chen L, et al. Diagnostic value of 5 serum biomarkers for hepatocellular carcinoma with different epide-miological backgrounds: a large-scale, retrospective study[J]. Cancer Biol Med, 2021, 18(1): 256-270. DOI: 10.20892/j.issn.2095-3941.2020.0207. doi: 10.20892/j.issn.2095-3941.2020.0207
[20]	Zhang J, Zhang M, Ma H, et al. Overexpression of glypican-3 is a predictor of poor prognosis in hepatocellular carcinoma: an updated meta-analysis[J]. Medicine (Baltimore), 2018, 97(24): e11130. DOI: 10.1097/MD.0000000000011130. doi: 10.1097/MD.0000000000011130
[21]	Si W, Shen J, Zheng H, et al. The role and mechanisms of action of microRNAs in cancer drug resistance[J]. Clin Epigenetics, 2019, 11(1): 25. DOI: 10.1186/s13148-018-0587-8. doi: 10.1186/s13148-018-0587-8
[22]	Zhou Y, Ren H, Dai B, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts[J]. J Exp Clin Cancer Res, 2018, 37(1): 324. DOI: 10.1186/s13046-018-0965-2. doi: 10.1186/s13046-018-0965-2
[23]	Ding Y, Yan JL, Fang AN, et al. Circulating miRNAs as novel diagnostic biomarkers in hepatocellular carcinoma detection: a meta-analysis based on 24 articles[J]. Oncotarget, 2017, 8(39): 66402-66413. DOI: 10.18632/oncotarget.18949. doi: 10.18632/oncotarget.18949 pmid: 29029522
[24]	Guo X, Lv X, Lv X, et al. Circulating miR-21 serves as a serum biomarker for hepatocellular carcinoma and correlated with distant metastasis[J]. Oncotarget, 2017, 8(27): 44050-44058. DOI: 10.18632/oncotarget.17211. doi: 10.18632/oncotarget.17211
[25]	Zhang H, Ding R, Chen D. Value of miR-21 levels as potential biomarkers in the early diagnosis of hepatocellular carcinoma: a meta-analysis[J]. Biomarkers, 2021, 26(7): 586-597. DOI: 10. 1080/1354750X.2021.1955976. doi: 10. 1080/1354750X.2021.1955976
[26]	Kong D, Wang X, Wang X, et al. Downregulated miRNA-22-3p promotes the progression and leads to poor prognosis of hepatocellular carcinoma through targeting CDKN2C[J]. J BUON, 2021, 26(2): 409-417.
[27]	Yamamoto Y, Kondo S, Matsuzaki J, et al. Highly sensitive circulating microRNA panel for accurate detection of hepato-cellular carcinoma in patients with liver disease[J]. Hepatol Commun, 2020, 4(2): 284-297. DOI: 10.1002/hep4.1451. doi: 10.1002/hep4.1451 pmid: 32025611
[28]	Fornari F, Pollutri D, Patrizi C, et al. In hepatocellular carcinoma miR-221 modulates sorafenib resistance through inhibition of caspase-3-mediated apoptosis[J]. Clin Cancer Res, 2017, 23(14): 3953-3965. DOI: 10.1158/1078-0432.CCR-16-1464. doi: 10.1158/1078-0432.CCR-16-1464
[29]	Okajima W, Komatsu S, Ichikawa D, et al. Liquid biopsy in patients with hepatocellular carcinoma: circulating tumor cells and cell-free nucleic acids[J]. World J Gastroenterol, 2017, 23(31): 5650-5668. DOI: 10.3748/wjg.v23.i31.5650. doi: 10.3748/wjg.v23.i31.5650
[30]	Chen J, Cao SW, Cai Z, et al. Epithelial-mesenchymal transition phenotypes of circulating tumor cells correlate with the clinical stages and cancer metastasis in hepatocellular carcinoma patients[J]. Cancer Biomark, 2017, 20(4): 487-498. DOI: 10.3233/CBM-170315. doi: 10.3233/CBM-170315
[31]	Court CM, Hou S, Winograd P, et al. A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepa-tocellular carcinoma[J]. Liver Transpl, 2018, 24(7): 946-960. DOI: 10.1002/lt.25062. doi: 10.1002/lt.25062
[32]	Qi LN, Xiang BD, Wu FX, et al. Circulating tumor cells under-going EMT provide a metric for diagnosis and prognosis of patients with hepatocellular carcinoma[J]. Cancer Res, 2018, 78(16): 4731-4744. DOI: 10.1158/0008-5472.CAN-17-2459. doi: 10.1158/0008-5472.CAN-17-2459
[33]	Ye Q, Ling S, Zheng S, et al. Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA[J]. Mol Cancer, 2019, 18(1): 114. DOI: 10.1186/s12943-019-1043-x. doi: 10.1186/s12943-019-1043-x
[34]	Yu JJ, Xiao W, Dong SL, et al. Effect of surgical liver resection on circulating tumor cells in patients with hepatocellular carcinoma[J]. BMC Cancer, 2018, 18(1): 835. DOI: 10.1186/s12885-018-4744-4. doi: 10.1186/s12885-018-4744-4
[35]	Wang PX, Xu Y, Sun YF, et al. Detection of circulating tumour cells enables early recurrence prediction in hepatocellular carcinoma patients undergoing liver transplantation[J]. Liver Int, 2021, 41(3): 562-573. DOI: 10.1111/liv.14734. doi: 10.1111/liv.14734
[36]	Wang Y, Zhou K, Wang X, et al. Multiple-level copy number variations in cell-free DNA for prognostic prediction of HCC with radical treatments[J]. Cancer Sci, 2021, 112(11): 4772-4784. DOI: 10.1111/cas.15128. doi: 10.1111/cas.15128
[37]	Xu RH, Wei W, Krawczyk M, et al. Circulating tumour DNA methy-lation markers for diagnosis and prognosis of hepatocellular carcinoma[J]. Nat Mater, 2017, 16(11): 1155-1161. DOI: 10. 1038/nmat4997. doi: 10. 1038/nmat4997
[38]	Ng CKY, Di Costanzo GG, Tosti N, et al. Genetic profiling using plasma-derived cell-free DNA in therapy-naïve hepatocellular carcinoma patients: a pilot study[J]. Ann Oncol, 2018, 29(5): 1286-1291. DOI: 10.1093/annonc/mdy083. doi: S0923-7534(19)34548-X pmid: 29509837
[39]	Jin C, Liu X, Zheng W, et al. Characterization of fragment sizes, copy number aberrations and 4-mer end motifs in cell-free DNA of hepatocellular carcinoma for enhanced liquid biopsy-based cancer detection[J]. Mol Oncol, 2021, 15(9): 2377-2389. DOI: 10.1002/1878-0261.13041. doi: 10.1002/1878-0261.13041