蛋白质糖基化修饰在肝细胞癌中的功能和临床意义

doi:10.11904/j.issn.1002-3070.2026.01.008

摘要/Abstract

摘要： 肝细胞癌(hepatocellular carcinoma,HCC)是全球范围内高发且预后较差的恶性肿瘤之一。蛋白质糖基化作为最丰富多样的翻译后修饰(post translational modification,PTM)形式之一,在HCC的发生、发展中发挥关键调控作用。本文系统综述了糖基化修饰的不同类型、调控机制及生物学功能,并阐述异常糖基化通过重塑细胞黏附、促进血管生成、调节代谢重编程及介导免疫逃逸等影响HCC恶性进展的作用机制。此外,本文还探讨了糖基化在HCC诊断、预后评估及靶向治疗中的转化潜力。最后,本文对未来糖基化研究方向进行展望,强调其在推动HCC精准医疗中的重要价值。

关键词: 肝细胞癌, 糖基化, 肿瘤微环境, 免疫逃逸, 靶向治疗

Abstract: Hepatocellular carcinoma(HCC)is one of the most prevalent and poorly prognostic malignant tumors globally.Protein glycosylation,as one of the most abundant and diverse forms of post-translational modification(PTM),plays a crucial regulatory role in the occurrence and progression of HCC.This article systematically reviews the different types,regulatory mechanisms and biological functions of glycosylation modifications,and elucidates the mechanisms by which abnormal glycosylation affects the malignant progression of HCC through remodeling cell adhesion,promoting angiogenesis,regulating metabolic reprogramming,and mediating immune escape.Furthermore,this article discusses the translational potential of glycosylation in the diagnosis,prognostic assessment,and targeted therapy of HCC.Finally,this article provides an outlook on future directions in glycosylation,emphasizing its significant value in advancing precision medicine for HCC.

Key words: hepatocellular carcinoma, glycosylation, tumor microenvironment, immune evasion, targeted therapy

中图分类号:

R735.7

全昕竹, 潘宇飞, 王红阳, 董立巍. 蛋白质糖基化修饰在肝细胞癌中的功能和临床意义[J]. 实用肿瘤学杂志, 2026, 40(1): 56-63.

QUAN Xinzhu, PAN Yufei, WANG Hongyang, DONG Liwei. Functional and clinical significance of protein glycosylation modification in hepatocellular[J]. Journal of Practical Oncology, 2026, 40(1): 56-63.

参考文献

1 辛鑫,熊文婧,张春暖,等.乳酸化修饰:癌症治疗中的新兴靶点[J].实用肿瘤学杂志,2025,39(5):433-436.
2 Qin J,Zhu W,Yang Z,et al.Post-translational modifications in hepatocellular carcinoma:mechanisms and therapeutic potential[J].Med Oncol,2025,42(11):524.
3 He M,Zhou X,and Wang X.Glycosylation:mechanisms,biological functions and clinical implications[J].Signal Transduct Target Ther,2024,9(1):194.
4 李薇,刘天华,张舒,等.肿瘤转移相关糖基转移酶表达调控研究进展[J].中国临床医学,2016,23(2):233-236.
5 Esmail S,Manolson MF.Advances in understanding N-glycosylation structure,function,and regulation in health and disease[J].Eur J Cell Biol,2021,100(7-8):151186.
6 李佳丽,宋泽庆,刘刚.蛋白质糖基化与疾病关系的研究进展[J].海南医学,2023,34(4):589-592.
7 Fu B,Chen J,Liu X,et al.Large-scale serum N-glycomics tracks N-glycosylation dynamics in hepatocellular carcinoma progression and enables early diagnosis[J].Nat Commun,2026.
8 Magalhães A,Duarte HO,and Reis CA.The role of O-glycosylation in human disease[J].Mol Aspects Med,2021,79:100964.
9 Zhou P,Chang WY,Gong DA,et al.High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-glcnacylation via microbiota-derived acetate[J].Cell Metab,2023,35(11):1961-1975.e1966.
10 Lin MC,Chuang YT,Wu HY,et al.Targeting tumor O-glycosylation modulates cancer-immune-cell crosstalk and enhances anti-PD-1 immunotherapy in head and neck cancer[J].Mol Oncol,2024,18(2):350-368.
11 Lundgren JG,Flynn MG,and List K.GPI-anchored serine proteases:essential roles in development,homeostasis,and disease[J].Biol Chem,2025,406(1-2):1-28.
12 Yang D,Han F,Cai J,et al.N-glycosylation by N-acetylglucosaminyltransferase IVa enhances the interaction of integrin β1 with vimentin and promotes hepatocellular carcinoma cell motility[J].Biochim Biophys Acta Mol Cell Res,2023,1870(7):119513.
13 Cui J,Huang W,Wu B,et al.N-glycosylation by N-acetylglucosaminyltransferase V enhances the interaction of CD147/basigin with integrin β1 and promotes HCC metastasis[J].J Pathol,2018,245(1):41-52.
14 Chen PD,Liao YY,Cheng YC,et al.Decreased B4GALT1 promotes hepatocellular carcinoma cell invasiveness by regulating the laminin-integrin pathway[J].Oncogenesis,2023,12(1):49.
15 Hu M,Zhang R,Yang J,et al.The role of N-glycosylation modification in the pathogenesis of liver cancer[J].Cell Death Dis,2023,14(3):222.
16 Leung Z,Ko FCF,Tey SK,et al.Galectin-1 promotes hepatocellular carcinoma and the combined therapeutic effect of OTX008 galectin-1 inhibitor and sorafenib in tumor cells[J].J Exp Clin Cancer Res,2019,38(1):423.
17 Song M,Pan Q,Yang J,et al.Galectin-3 favours tumour metastasis via the activation of β-catenin signalling in hepatocellular carcinoma[J].Br J Cancer,2020,123(10):1521-1534.
18 Li H,Wu K,Tao K,et al.Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma[J].Hepatology,2012,56(4):1342-1351.
19 Fujita K,Iwama H,Sakamoto T,et al.Galectin-9 suppresses the growth of hepatocellular carcinoma via apoptosis in vitro and in vivo[J].Int J Oncol,2015,46(6):2419-2430.
20 Jiao J,Jiao D,Yang F,et al.Galectin-9 expression predicts poor prognosis in hepatitis B virus-associated hepatocellular carcinoma[J].Aging(Albany NY),2022,14(4):1879-1890.
21 Sideras K,Biermann K,Verheij J,et al.PD-L1,galectin-9 and CD8(+)tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma[J].Oncoimmunology,2017,6(2):e1273309.
22 Chen S,Pu J,Bai J,et al.EZH2 promotes hepatocellular carcinoma progression through modulating miR-22/galectin-9 axis[J].J Exp Clin Cancer Res,2018,37(1):3.
23 Sideras K,de Man RA,Harrington SM,et al.Circulating levels of PD-L1 and galectin-9 are associated with patient survival in surgically treated hepatocellular carcinoma independent of their intra-tumoral expression levels[J].Sci Rep,2019,9(1):10677.
24 Lee TA,Tsai EY,Liu SH,et al.Regulation of PD-L1 glycosylation and advances in cancer immunotherapy[J].Cancer Lett,2025,612:217498.
25 Duan Z,Shi R,Gao B,et al.N-linked glycosylation of PD-L1/PD-1:an emerging target for cancer diagnosis and treatment[J].J Transl Med,2024,22(1):705.
26 Mao Z,Mu J,Gao Z,et al.Biological functions and potential therapeutic significance of O-glcnacylation in hepatic cellular stress and liver diseases[J].Cells,2024,13(10):805.
27 Zhu Q,Wang H,Chai S,et al.O-glcnacylation promotes tumor immune evasion by inhibiting PD-L1 lysosomal degradation[J].Proc Natl Acad Sci U S A,2023,120(13):e2216796120.
28 Xiao R,Tian Y,Zhang J,et al.Increased siglec-9/siglec-9L interactions on NK cells predict poor HCC prognosis and present a targetable checkpoint for immunotherapy[J].J Hepatol,2024,80(5):792-804.
29 Radovani B,Gudelj I.N-glycosylation and inflammation;the not-so-sweet relation[J].Front Immunol,2022,13:893365.
30 Islam M,Arlian BM,Pfrengle F,et al.Suppressing immune responses using siglec ligand-decorated anti-receptor antibodies[J].J Am Chem Soc,2022,144(21):9302-9311.
31 Altevogt P,Sammar M,Hüser L,et al.Novel insights into the function of CD24:a driving force in cancer[J].Int J Cancer,2021,148(3):546-559.
32 Zhang Y,He B,Zou P,et al.Targeted release of a bispecific fusion protein SIRPα/siglec-10 by oncolytic adenovirus reinvigorates tumor-associated macrophages to improve therapeutic outcomes in solid tumors[J].J Immunother Cancer,2025,13(4).
33 Barkal AA,Brewer RE,Markovic M,et al.CD24 signalling through macrophage siglec-10 is a target for cancer immunotherapy[J].Nature,2019,572(7769):392-396.
34 Jiang S,Li H,Zhang L,et al.Generic diagramming platform(GDP):a comprehensive database of high-quality biomedical graphics[J].Nucleic Acids Res,2025,53(D1):D1670-d1676.
35 Lin Y,Lubman DM.The role of N-glycosylation in cancer[J].Acta Pharm Sin B,2024,14(3):1098-1110.
36 Schepers EJ,Glaser K,Zwolshen HM,et al.Structural and functional impact of posttranslational modification of glypican-3 on liver carcinogenesis[J].Cancer Res,2023,83(12):1933-1940.
37 Man XB,Tang L,Zhang BH,et al.Upregulation of glypican-3 expression in hepatocellular carcinoma but downregulation in cholangiocarcinoma indicates its differential diagnosis value in primary liver cancers[J].Liver Int,2005,25(5):962-966.
38 Zhang Y,Li J,Huang Y,et al.Improved antitumor activity against prostate cancer via synergistic targeting of Myc and GFAT-1[J].Theranostics,2023,13(2):578-595.
39 Wang M,Zhang Z,Chen M,et al.FDW028,a novel FUT8 inhibitor,impels lysosomal proteolysis of B7-H3 via chaperone-mediated autophagy pathway and exhibits potent efficacy against metastatic colorectal cancer[J].Cell Death Dis,2023,14(8):495.
40 Shi D,Shi Y,Kaseb AO,et al.Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma:results of phase I trials[J].Clin Cancer Res,2020,26(15):3979-3989.
41 Dou WT,Guo C,Zhu L,et al.Targeted near-infrared fluorescence imaging of liver cancer using dual-peptide-functionalized albumin particles[J].Chem Biomed Imaging,2024,2(1):47-55.
42 Li CW,Lim SO,Chung EM,et al.Eradication of triple-negative breast cancer cells by targeting glycosylated PD-L1[J].Cancer Cell,2018,33(2):187-201.e110.
43 Lee HH,Wang YN,Xia W,et al.Removal of N-linked glycosylation enhances PD-L1 detection and predicts anti-PD-1/PD-L1 therapeutic efficacy[J].Cancer Cell,2019,36(2):168-178.e164.
44 Posey AD Jr,Schwab RD,Boesteanu AC,et al.Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma[J].Immunity,2016,44(6):1444-1454.
45 Yankelevich M,Thakur A,Modak S,et al.Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3×anti-GD2 bispecific antibody armed T cells[J].J Immunother Cancer,2024,12(3):e008744.

[1]	赵凤娟, 农小莲, 黄仕环, 李繁荣, 卢飞臣, 游雪梅. 问题解决疗法对中晚期肝癌免疫治疗患者抑郁情绪、生活质量及疗效的影响:一项随机对照试验[J]. 实用肿瘤学杂志, 2026, 40(1): 30-40.
[2]	蔡意好, 赵俊皓, 赵金璐, 刘明. SLC1A4在不同恶性肿瘤中作用的研究进展[J]. 实用肿瘤学杂志, 2026, 40(1): 69-74.
[3]	赵志龙, 侯俊明. 细胞外基质在胰腺癌中的作用机制及治疗靶点研究进展[J]. 实用肿瘤学杂志, 2025, 39(6): 535-541.
[4]	蔡医擎, 代恩勇. 胃癌分子靶向治疗的研究进展[J]. 实用肿瘤学杂志, 2025, 39(6): 542-550.
[5]	辛鑫, 熊文婧, 张春暖, 李晓静, 高雪, 张悦. 乳酸化修饰:癌症治疗中的新兴靶点[J]. 实用肿瘤学杂志, 2025, 39(5): 433-436.
[6]	李冬生, 李泽昊, 陈永刚. 铁死亡相关基因的DNA甲基化风险评分模型在结肠癌预后与免疫特征评估中的应用[J]. 实用肿瘤学杂志, 2025, 39(3): 224-234.
[7]	叶倩妮, 李娟, 王发琳, 刘家仁. 植物化学物在肿瘤微环境中的作用研究进展[J]. 实用肿瘤学杂志, 2025, 39(3): 245-250.
[8]	朱磊, 郝丹丹. 非编码RNA调控铁死亡介导肝细胞癌索拉非尼耐药的研究进展[J]. 实用肿瘤学杂志, 2025, 39(3): 256-261.
[9]	关勇宇, 聂昊, 张翀. 肝细胞癌小鼠模型构建的研究进展[J]. 实用肿瘤学杂志, 2024, 38(5): 342-348.
[10]	邵禹铭, 朱坤兵, 张洁. SP/NK-1R系统在乳腺癌中的研究进展[J]. 实用肿瘤学杂志, 2024, 38(4): 268-272.
[11]	黑龙江省医学会乳腺肿瘤学组. 黑龙江省乳腺癌HER2低表达临床病理诊断专家共识(2024版)[J]. 实用肿瘤学杂志, 2024, 38(2): 71-78.
[12]	庞武, 陈莉江, 朱宇, 吴涯昆, 张伟. 血清miRNA-24和miRNA-509在肝细胞癌患者血清中的表达及与预后的关系[J]. 实用肿瘤学杂志, 2023, 37(5): 411-415.
[13]	樊婷婷, 丁丹妮, 赵子雪, 于洋, 韩凤娟. 脂肪酸代谢与卵巢癌[J]. 实用肿瘤学杂志, 2023, 37(5): 429-433.
[14]	罗汀繁, 孙鹏飞. 巨噬细胞/小胶质细胞在胶质瘤微环境中的研究进展[J]. 实用肿瘤学杂志, 2023, 37(5): 443-448.
[15]	曹莹月, 庞露薏, 张键, 金时. 癌相关成纤维细胞在非小细胞肺癌进展中的作用[J]. 实用肿瘤学杂志, 2023, 37(4): 383-388.