中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 41 Issue 11
Nov.  2025
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2025  >  41(11): 2435-2440

The role and mechanism of heparanase in hepatobiliary and pancreatic tumors

DOI: 10.12449/JCH251136
  • 1.

    The First Clinical Medical College of Gansu University of Chinese Medicine，Lanzhou 730000，China

  • 2.

    Department of Gastroenterology，The 940 Hospital of Joint Logistic Support Force of PLA，Lanzhou 730050，China

  • 3.

    Department of Gastroenterology，The Fifth People’s Hospital of Ganzhou，Ganzhou，Jiangxi 341000，China

Research funding:

Gansu Province Health and Wellness Industry Research Plan Project (GSWSKY2023-34);

Gansu University of Chinese Medicine Supervisor Special Project (2023YXKY020);

Lanzhou City Youth Science and Technology Talent Innovation Project (2024-QN-39)

More Information
  • Corresponding author: ZHANG Jiucong， zhangjiucong@163.com （ORCID： 0000-0003-4006-3033）; LIANG Bin， 123450632@qq.com （ORCID： 0000-0003-4427-8445）
  • Received Date: 2025-03-17
  • Accepted Date: 2025-05-12
  • Published Date: 2025-11-25
    Abstract
  • Hepatobiliary and pancreatic tumors are common types of digestive system disorders， and their complex pathogeneses have led to difficulties in early diagnosis and a high metastasis rate， with persistently high incidence and mortality rates in China， which greatly affects the quality of life and prognosis of patients. Studies have shown that heparanase （HPSE）， as a key effector molecule in matrix remodeling， plays a crucial regulatory role in tumor invasion and metastasis and microenvironment remodeling， and it is significantly associated with clinical prognosis. This article reviews the molecular mechanism of HPSE in hepatobiliary and pancreatic tumors， in order to provide a strong scientific basis for developing diagnostic markers and targeted interventions for hepatobiliary and pancreatic tumors.

     

    • FullText(HTML)
  • loading
    • References(51)
  • [1]
    MINAMI K, MORIMOTO H, MORIOKA H, et al. Pathogenic roles of heparan sulfate and its use as a biomarker in mucopolysaccharidoses[J]. Int J Mol Sci, 2022, 23( 19): 11724. DOI: 10.3390/ijms231911724.
    [2]
    LING JX, LI JL, KHAN A, et al. Is heparan sulfate a target for inhibition of RNA virus infection?[J]. Am J Physiol Cell Physiol, 2022, 322( 4): C605- C613. DOI: 10.1152/ajpcell.00028.2022.
    [3]
    ALSHEHRI MA, ALSHEHRI MM, ALBALAWI NN, et al. Heparan sulfate proteoglycans and their modification as promising anticancer targets in hepatocellular carcinoma[J]. Oncol Lett, 2021, 21( 2): 173. DOI: 10.3892/ol.2021.12434.
    [4]
    FOOTE CA, SOARES RN, RAMIREZ-PEREZ FI, et al. Endothelial glycocalyx[J]. Compr Physiol, 2022, 12( 4): 3781- 3811. DOI: 10.1002/cphy.c210029.
    [5]
    ZAHAVI T, SALMON-DIVON M, SALGADO R, et al. Heparanase: A potential marker of worse prognosis in estrogen receptor-positive breast cancer[J]. NPJ Breast Cancer, 2021, 7( 1): 67. DOI: 10.1038/s41523-021-00277-x.
    [6]
    FARIA-RAMOS I, POÇAS J, MARQUES C, et al. Heparan sulfate glycosaminoglycans:(un)expected allies in cancer clinical management[J]. Biomolecules, 2021, 11( 2): 136. DOI: 10.3390/biom11020136.
    [7]
    SAAD F, GADALLAH M, DAIF A, et al. Heparanase(HPSE) gene polymorphism(rs12503843) contributes as a risk factor for hepatocellular carcinoma(HCC): A pilot study among Egyptian patients[J]. J Genet Eng Biotechnol, 2021, 19( 1): 3. DOI: 10.1186/s43141-020-00106-x.
    [8]
    YUAN FY, YANG YY, ZHOU HQ, et al. Heparanase in cancer progression: Structure, substrate recognition and therapeutic potential[J]. Front Chem, 2022, 10: 926353. DOI: 10.3389/fchem.2022.926353.
    [9]
    BARTOLINI B, CARAVÀ E, CAON I, et al. Heparan sulfate in the tumor microenvironment[J]. Adv Exp Med Biol, 2020, 1245: 147- 161. DOI: 10.1007/978-3-030-40146-7_7.
    [10]
    KOGANTI R, SURYAWANSHI R, SHUKLA D. Heparanase, cell signaling, and viral infections[J]. Cell Mol Life Sci, 2020, 77( 24): 5059- 5077. DOI: 10.1007/s00018-020-03559-y.
    [11]
    MASOLA V, ZAZA G, GAMBARO G, et al. Role of heparanase in tumor progression: Molecular aspects and therapeutic options[J]. Semin Cancer Biol, 2020, 62: 86- 98. DOI: 10.1016/j.semcancer.2019.07.014.
    [12]
    MAYFOSH AJ, NGUYEN TK, HULETT MD. The heparanase regulatory network in health and disease[J]. Int J Mol Sci, 2021, 22( 20): 11096. DOI: 10.3390/ijms222011096.
    [13]
    VLODAVSKY I, KAYAL Y, HILWI M, et al. Heparanase-A single protein with multiple enzymatic and nonenzymatic functions[J]. Proteoglycan Res, 2023, 1( 3): e6. DOI: 10.1002/pgr2.6.
    [14]
    YANG YY, YUAN FY, ZHOU HQ, et al. Potential roles of heparanase in cancer therapy: Current trends and future direction[J]. J Cell Physiol, 2023, 238( 5): 896- 917. DOI: 10.1002/jcp.30995.
    [15]
    PAPE T, HUNKEMÖLLER AM, KÜMPERS P, et al. Targeting the“sweet spot” in septic shock- A perspective on the endothelial glycocalyx regulating proteins Heparanase-1 and-2[J]. Matrix Biol Plus, 2021, 12: 100095. DOI: 10.1016/j.mbplus.2021.100095.
    [16]
    LIU JJ, KNANI I, GROSS-COHEN M, et al. Role of heparanase 2(Hpa2) in gastric cancer[J]. Neoplasia, 2021, 23( 9): 966- 978. DOI: 10.1016/j.neo.2021.07.010.
    [17]
    HOPKINS J, VOLETY I, QATANANI F, et al. Heparanase 2 modulation inhibits HSV-2 replication by regulating heparan sulfate[J]. Viruses, 2024, 16( 12): 1832. DOI: 10.3390/v16121832.
    [18]
    KHANNA M, PARISH CR. Heparanase: Historical aspects and future perspectives[J]. Adv Exp Med Biol, 2020, 1221: 71- 96. DOI: 10.1007/978-3-030-34521-1_3.
    [19]
    VLODAVSKY I, ILAN N, SANDERSON RD. Forty years of basic and translational heparanase research[J]. Adv Exp Med Biol, 2020, 1221: 3- 59. DOI: 10.1007/978-3-030-34521-1_1.
    [20]
    GROSS-COHEN M, YANKU Y, KESSLER O, et al. Heparanase 2(Hpa2) attenuates tumor growth by inducing Sox2 expression[J]. Matrix Biol, 2021, 99: 58- 71. DOI: 10.1016/j.matbio.2021.05.001.
    [21]
    BECKER Y, HALLER H. Current understanding of heparanase 2 regulation, a non-heparanase[J]. Biochem Soc Trans, 2025, 53( 1): BST 2024‑1281. DOI: 10.1042/BST20241281.
    [22]
    KALONI D, DIEPSTRATEN ST, STRASSER A, et al. BCL-2 protein family: Attractive targets for cancer therapy[J]. Apoptosis, 2023, 28( 1-2): 20- 38. DOI: 10.1007/s10495-022-01780-7.
    [23]
    KNANI I, SINGH P, GROSS-COHEN M, et al. Induction of heparanase 2(Hpa2) expression by stress is mediated by ATF3[J]. Matrix Biol, 2022, 105: 17- 30. DOI: 10.1016/j.matbio.2021.11.001.
    [24]
    SOBOH S, VORONTSOVA A, FARHOUD M, et al. Tumor- and host-derived heparanase-2(Hpa2) attenuates tumorigenicity: Role of Hpa2 in macrophage polarization and BRD7 nuclear localization[J]. Cell Death Dis, 2024, 15( 12): 894. DOI: 10.1038/s41419-024-07262-9.
    [25]
    ZHANG GL, GUTTER-KAPON L, ILAN N, et al. Significance of host heparanase in promoting tumor growth and metastasis[J]. Matrix Biol, 2020, 93: 25- 42. DOI: 10.1016/j.matbio.2020.06.001.
    [26]
    SHAH M, SARKAR D. HCC-related lncRNAs: Roles and mechanisms[J]. Int J Mol Sci, 2024, 25( 1): 597. DOI: 10.3390/ijms25010597.
    [27]
    CHEN XP, CHENG B, DAI DF, et al. Heparanase induces necroptosis of microvascular endothelial cells to promote the metastasis of hepatocellular carcinoma[J]. Cell Death Discov, 2021, 7( 1): 33. DOI: 10.1038/s41420-021-00411-5.
    [28]
    RESZEGI A, TÁTRAI P, REGŐS E, et al. Syndecan-1 in liver pathophysiology[J]. Am J Physiol Cell Physiol, 2022, 323( 2): C289- C294. DOI: 10.1152/ajpcell.00039.2022.
    [29]
    ZHANG XL, ZHAO YL, LIU LR, et al. Syndecan-1: A novel diagnostic and therapeutic target in liver diseases[J]. Curr Drug Targets, 2023, 24( 15): 1155- 1165. DOI: 10.2174/0113894501250057231102061624.
    [30]
    YANG R, CHEN MM, ZHENG JY, et al. The role of heparin and glycocalyx in blood-brain barrier dysfunction[J]. Front Immunol, 2021, 12: 754141. DOI: 10.3389/fimmu.2021.754141.
    [31]
    ARDIZZONE A, BOVA V, CASILI G, et al. Role of basic fibroblast growth factor in cancer: Biological activity, targeted therapies, and prognostic value[J]. Cells, 2023, 12( 7): 1002. DOI: 10.3390/cells1207-1002.
    [32]
    GALLARD C, LEBSIR N, KHURSHEED H, et al. Heparanase-1 is upregulated by hepatitis C virus and favors its replication[J]. J Hepatol, 2022, 77( 1): 29- 41. DOI: 10.1016/j.jhep.2022.01.008.
    [33]
    FENG F, WANG LJ, LI JC, et al. Role of heparanase in ARDS through autophagy and exosome pathway(review)[J]. Front Pharmacol, 2023, 14: 1200782. DOI: 10.3389/fphar.2023.1200782.
    [34]
    DAVID G, ZIMMERMANN P. Heparanase involvement in exosome formation[J]. Adv Exp Med Biol, 2020, 1221: 285- 307. DOI: 10.1007/978-3-030-34521-1_10.
    [35]
    van der VLAG J, BUIJSERS B. Heparanase in kidney disease[J]. Adv Exp Med Biol, 2020, 1221: 647- 667. DOI: 10.1007/978-3-030-34521-1_26.
    [36]
    YANG CG, DOU RZ, WEI C, et al. Tumor-derived exosomal microRNA-106b-5p activates EMT-cancer cell and M2-subtype TAM interaction to facilitate CRC metastasis[J]. Mol Ther, 2021, 29( 6): 2088- 2107. DOI: 10.1016/j.ymthe.2021.02.006.
    [37]
    BRAGAZZI MC, VENERE R, RIBICHINI E, et al. Intrahepatic cholangiocarcinoma: Evolving strategies in management and treatment[J]. Dig Liver Dis, 2024, 56( 3): 383- 393. DOI: 10.1016/j.dld.2023.08.052.
    [38]
    YUAN FY, ZHOU HQ, LIU CY, et al. Heparanase interacting BCLAF1 to promote the development and drug resistance of ICC through the PERK/eIF2α pathway[J]. Cancer Gene Ther, 2024, 31( 6): 904- 916. DOI: 10.1038/s41417-024-00754-y.
    [39]
    HALBROOK CJ, LYSSIOTIS CA, PASCA DI MAGLIANO M, et al. Pancreatic cancer: Advances and challenges[J]. Cell, 2023, 186( 8): 1729- 1754. DOI: 10.1016/j.cell.2023.02.014.
    [40]
    XUE WH, YANG L, CHEN CX, et al. Wnt/β-catenin-driven EMT regulation in human cancers[J]. Cell Mol Life Sci, 2024, 81( 1): 79. DOI: 10.1007/s00018-023-05099-7.
    [41]
    WANG C, WEI YJ, WANG G, et al. Heparanase potentiates the invasion and migration of pancreatic cancer cells via epithelial-to-mesenchymal transition through the Wnt/β-catenin pathway[J]. Oncol Rep, 2020, 44( 2): 711- 721. DOI: 10.3892/or.2020.7641.
    [42]
    ABECASSIS A, HERMANO E, YIFRACH A, et al. Heparanase contributes to pancreatic carcinoma progression through insulin-dependent glucose uptake[J]. Front Cell Dev Biol, 2023, 11: 1287084. DOI: 10.3389/fcell.2023.1287084.
    [43]
    ZHANG H, XU CX, SHI C, et al. Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis[J]. J Transl Med, 2021, 19( 1): 98. DOI: 10.1186/s12967-021-02770-0.
    [44]
    KAYAL Y, BARASH U, NARODITSKY I, et al. Heparanase 2(Hpa2)- a new player essential for pancreatic acinar cell differentiation[J]. Cell Death Dis, 2023, 14( 7): 465. DOI: 10.1038/s41419-023-05990-y.
    [45]
    VLODAVSKY I, HILWI M, KAYAL Y, et al. Impact of heparanase-2(Hpa2) on cancer and inflammation: Advances and paradigms[J]. FASEB J, 2024, 38( 10): e23670. DOI: 10.1096/fj.202400286R.
    [46]
    CASSINELLI G, TORRI G, NAGGI A. Non-anticoagulant heparins as heparanase inhibitors[J]. Adv Exp Med Biol, 2020, 1221: 493- 522. DOI: 10.1007/978-3-030-34521-1_20.
    [47]
    ZHANG YZ, XIONG MJ, CHEN ZX, et al. Design principle of heparanase inhibitors: A combined in vitro and in silico study[J]. ACS Med Chem Lett, 2024, 15( 7): 1032- 1040. DOI: 10.1021/acsmedchemlett.3c00268.
    [48]
    ZHANG YZ, CUI LN. Discovery and development of small-molecule heparanase inhibitors[J]. Bioorg Med Chem, 2023, 90: 117335. DOI: 10.1016/j.bmc.2023.117335.
    [49]
    RUS A, BOLANOS-GARCIA VM, BASTIDA A, et al. Identification of novel potential heparanase inhibitors using virtual screening[J]. Catalysts, 2022, 12( 5): 503. DOI: 10.3390/catal12050503.
    [50]
    LEBSIR N, ZOULIM F, GRIGOROV B. Heparanase-1: From cancer biology to a future antiviral target[J]. Viruses, 2023, 15( 1): 237. DOI: 10.3390/v15010237.
    [51]
    de BOER C, ARMSTRONG Z, LIT VAJ, et al. Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo[J]. Proc Natl Acad Sci USA, 2022, 119( 31): e2203167119. DOI: 10.1073/pnas.2203167119.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(1)  / Tables(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (2) PDF downloads(2) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return