HSPG2在恶性肿瘤中的功能机制及其作为治疗靶点的潜力
The Functional Mechanism of HSPG2 in Malignant Tumors and Its Potential as a Therapeutic Target
摘要: 在细胞外微环境中，硫酸肝素蛋白多糖(Heparan Sulfate Proteoglycans, HSPGs)是一类具有结构多样性的基质相关分子。其基本组成包括核心蛋白以及通过共价键连接的硫酸肝素(Heparan Sulfate, HS)侧链，不同的修饰模式赋予其高度异质性。正是这种结构复杂性，使HSPGs不仅参与生长因子的结合与储存，还能够协助受体复合物形成，调节信号传递效率，从而影响细胞增殖调控、迁移行为以及血管生成等多种生物学事件。作为该家族中分子量最大、结构域最为复杂的成员之一，HSPG2在基底膜结构维持中占据重要地位。已有研究表明，它不仅参与胚胎发育阶段的组织构建，也在成年组织稳态维持中发挥持续性调控作用。近年来，关于HSPG2的肿瘤相关研究逐渐增多。越来越多的证据提示，其表达水平异常常见于多种实体瘤以及血液系统恶性疾病。功能层面上，HSPG2可通过重塑肿瘤微环境、增强生长因子信号活性以及调节细胞与细胞外基质之间的相互作用，推动肿瘤进展。总体来看，HSPG2更像是连接细胞外结构与胞内信号转导体系的功能枢纽。围绕其结构特征、翻译后修饰状态及其与特定信号通路之间的相互调控关系展开深入研究，将有助于深化对肿瘤分子机制的理解，并为靶向干预策略的探索提供新的思路。
Abstract: Heparan sulfate proteoglycans (HSPGs) are structurally diverse matrix-associated molecules within the extracellular microenvironment. Composed of a core protein covalently linked to heparan sulfate (HS) chains, their heterogeneous modification patterns enable them to bind growth factors, facilitate receptor complex formation, and regulate signaling activity, thereby influencing cell proliferation, migration, and angiogenesis. HSPG2 (Perlecan), one of the largest and most structurally complex members of this family, is essential for basement membrane integrity and tissue homeostasis, with established roles in both embryonic development and adult physiology. Increasing evidence indicates that aberrant HSPG2 expression is frequently observed in solid tumors and hematological malignancies, where it contributes to tumor progression through modulation of the tumor microenvironment and growth factor-dependent signaling. Overall, HSPG2 functions as a molecular hub linking extracellular matrix architecture to intracellular signaling pathways, making it a promising focus for mechanistic studies and targeted therapeutic exploration.
文章引用：何林醒, 王青云, 孙锋. HSPG2在恶性肿瘤中的功能机制及其作为治疗靶点的潜力[J]. 临床个性化医学, 2026, 5(2): 602-611. https://doi.org/10.12677/jcpm.2026.52162

参考文献

[1] Farach-Carson, M.C., Warren, C.R., Harrington, D.A. and Carson, D.D. (2014) Border Patrol: Insights into the Unique Role of Perlecan/Heparan Sulfate Proteoglycan 2 at Cell and Tissue Borders. Matrix Biology, 34, 64-79. [Google Scholar] [CrossRef] [PubMed]
[2] Ravikumar, M., Smith, R.A.A., Nurcombe, V. and Cool, S.M. (2020) Heparan Sulfate Proteoglycans: Key Mediators of Stem Cell Function. Frontiers in Cell and Developmental Biology, 8, Article 581213. [Google Scholar] [CrossRef] [PubMed]
[3] Bork, P. and Patthy, L. (1995) The SEA Module: A New Extracellular Domain Associated with O-Glycosylation. Protein Science, 4, 1421-1425. [Google Scholar] [CrossRef] [PubMed]
[4] Greco, N., Masola, V. and Onisto, M. (2025) Heparan Sulfate Proteoglycans (HSPGs) and Their Degradation in Health and Disease. Biomolecules, 15, Article 1597. [Google Scholar] [CrossRef] 
[5] Sarrazin, S., Lamanna, W.C. and Esko, J.D. (2011) Heparan Sulfate Proteoglycans. Cold Spring Harbor Perspectives in Biology, 3, a004952. [Google Scholar] [CrossRef] [PubMed]
[6] Mayfosh, A.J., Nguyen, T.K. and Hulett, M.D. (2021) The Heparanase Regulatory Network in Health and Disease. International Journal of Molecular Sciences, 22, Article 11096. [Google Scholar] [CrossRef] [PubMed]
[7] Cohen, I.R., Grässel, S., Murdoch, A.D. and Iozzo, R.V. (1993) Structural Characterization of the Complete Human Perlecan Gene and Its Promoter. Proceedings of the National Academy of Sciences, 90, 10404-10408. [Google Scholar] [CrossRef] [PubMed]
[8] Graham, L.D., Whitelock, J.M. and Underwood, P.A. (1999) Expression of Human Perlecan Domain I as a Recombinant Heparan Sulfate Proteoglycan with 20-kDa Glycosaminoglycan Chains. Biochemical and Biophysical Research Communications, 256, 542-548. [Google Scholar] [CrossRef] [PubMed]
[9] Paulsson, M., Yurchenco, P.D., Ruben, G.C., Engel, J. and Timpl, R. (1987) Structure of Low Density Heparan Sulfate Proteoglycan Isolated from a Mouse Tumor Basement Membrane. Journal of Molecular Biology, 197, 297-313. [Google Scholar] [CrossRef] [PubMed]
[10] Zhou, Z., Wang, J., Cao, R., Morita, H., Soininen, R., Chan, K.M., et al. (2004) Impaired Angiogenesis, Delayed Wound Healing and Retarded Tumor Growth in Perlecan Heparan Sulfate-Deficient Mice. Cancer Research, 64, 4699-4702. [Google Scholar] [CrossRef] [PubMed]
[11] Gubbiotti, M.A., Neill, T. and Iozzo, R.V. (2017) A Current View of Perlecan in Physiology and Pathology: A Mosaic of Functions. Matrix Biology, 57, 285-298. [Google Scholar] [CrossRef] [PubMed]
[12] Martinez, J.R., Dhawan, A. and Farach-Carson, M.C. (2018) Modular Proteoglycan Perlecan/HSPG2: Mutations, Phenotypes, and Functions. Genes, 9, Article 556. [Google Scholar] [CrossRef] [PubMed]
[13] Smith, S.M.L., West, L.A. and Hassell, J.R. (2007) The Core Protein of Growth Plate Perlecan Binds FGF-18 and Alters Its Mitogenic Effect on Chondrocytes. Archives of Biochemistry and Biophysics, 468, 244-251. [Google Scholar] [CrossRef] [PubMed]
[14] Hopf, M., Göhring, W., Kohfeldt, E., Yamada, Y. and Timpl, R. (1999) Recombinant Domain IV of Perlecan Binds to Nidogens, Laminin-Nidogen Complex, Fibronectin, Fibulin-2 and Heparin. European Journal of Biochemistry, 259, 917-926. [Google Scholar] [CrossRef] [PubMed]
[15] Mongiat, M., Sweeney, S.M., San Antonio, J.D., Fu, J. and Iozzo, R.V. (2003) Endorepellin, a Novel Inhibitor of Angiogenesis Derived from the C Terminus of Perlecan. Journal of Biological Chemistry, 278, 4238-4249. [Google Scholar] [CrossRef] [PubMed]
[16] Douglass, S., Goyal, A. and Iozzo, R.V. (2015) The Role of Perlecan and Endorepellin in the Control of Tumor Angiogenesis and Endothelial Cell Autophagy. Connective Tissue Research, 56, 381-391. [Google Scholar] [CrossRef] [PubMed]
[17] Annaval, T., Wild, R., Crétinon, Y., Sadir, R., Vivès, R.R. and Lortat-Jacob, H. (2020) Heparan Sulfate Proteoglycans Biosynthesis and Post Synthesis Mechanisms Combine Few Enzymes and Few Core Proteins to Generate Extensive Structural and Functional Diversity. Molecules, 25, Article 4215. [Google Scholar] [CrossRef] [PubMed]
[18] Bishop, J.R., Schuksz, M. and Esko, J.D. (2007) Heparan Sulphate Proteoglycans Fine-Tune Mammalian Physiology. Nature, 446, 1030-1037. [Google Scholar] [CrossRef] [PubMed]
[19] Ornitz, D.M. (2000) FGFs, Heparan Sulfate and FGFRs: Complex Interactions Essential for Development. BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology, 22, 108-112. [Google Scholar] [CrossRef] [PubMed]
[20] Yayon, A., Klagsbrun, M., Esko, J.D., Leder, P. and Ornitz, D.M. (1991) Cell Surface, Heparin-Like Molecules Are Required for Binding of Basic Fibroblast Growth Factor to Its High Affinity Receptor. Cell, 64, 841-848. [Google Scholar] [CrossRef] [PubMed]
[21] Choi, Y., Chung, H., Jung, H., Couchman, J.R. and Oh, E.S. (2011) Syndecans as Cell Surface Receptors: Unique Structure Equates with Functional Diversity. Matrix Biology, 30, 93-99. [Google Scholar] [CrossRef] [PubMed]
[22] Kramer, K.L. and Yost, H.J. (2003) Heparan Sulfate Core Proteins in Cell-Cell Signaling. Annual Review of Genetics, 37, 461-484. [Google Scholar] [CrossRef] [PubMed]
[23] Kramer, K.L. and Yost, H.J. (2002) Ectodermal Syndecan-2 Mediates Left-Right Axis Formation in Migrating Mesoderm as a Cell-Nonautonomous Vg1 Cofactor. Developmental Cell, 2, 115-124. [Google Scholar] [CrossRef] [PubMed]
[24] Belting, M. (2003) Heparan Sulfate Proteoglycan as a Plasma Membrane Carrier. Trends in Biochemical Sciences, 28, 145-151. [Google Scholar] [CrossRef] [PubMed]
[25] Wittrup, A., Zhang, S., Svensson, K.J., Kucharzewska, P., Johansson, M.C., Mörgelin, M., et al. (2010) Magnetic Nanoparticle-Based Isolation of Endocytic Vesicles Reveals a Role of the Heat Shock Protein GRP75 in Macromolecular Delivery. Proceedings of the National Academy of Sciences, 107, 13342-13347. [Google Scholar] [CrossRef] [PubMed]
[26] Poon, G.M. and Gariépy, J. (2007) Cell-Surface Proteoglycans as Molecular Portals for Cationic Peptide and Polymer Entry into Cells. Biochemical Society Transactions, 35, 788-793.
[27] French, M.M., Smith, S.E., Akanbi, K., Sanford, T., Hecht, J., Farach-Carson, M.C., et al. (1999) Expression of the Heparan Sulfate Proteoglycan, Perlecan, during Mouse Embryogenesis and Perlecan Chondrogenic Activity in Vitro. The Journal of Cell Biology, 145, 1103-1115. [Google Scholar] [CrossRef] [PubMed]
[28] Stum, M., Girard, E., Bangratz, M., Bernard, V., Herbin, M., Vignaud, A., et al. (2008) Evidence of a Dosage Effect and a Physiological Endplate Acetylcholinesterase Deficiency in the First Mouse Models Mimicking Schwartz-Jampel Syndrome Neuromyotonia. Human Molecular Genetics, 17, 3166-3179. [Google Scholar] [CrossRef] [PubMed]
[29] Kaneko, H., Ishijima, M., Futami, I., Tomikawa-Ichikawa, N., Kosaki, K., Sadatsuki, R., et al. (2013) Synovial Perlecan Is Required for Osteophyte Formation in Knee Osteoarthritis. Matrix Biology, 32, 178-187. [Google Scholar] [CrossRef] [PubMed]
[30] Martinez, J.R., Grindel, B.J., Hubka, K.M., Dodge, G.R. and Farach-Carson, M.C. (2019) Perlecan/HSPG2: Signaling Role of Domain IV in Chondrocyte Clustering with Implications for Schwartz-Jampel Syndrome. Journal of Cellular Biochemistry, 120, 2138-2150. [Google Scholar] [CrossRef] [PubMed]
[31] Johnson, B.B., Cosson, M., Tsansizi, L.I., Holmes, T.L., Gilmore, T., Hampton, K., et al. (2024) Perlecan (HSPG2) Promotes Structural, Contractile, and Metabolic Development of Human Cardiomyocytes. Cell Reports, 43, Article 113668. [Google Scholar] [CrossRef] [PubMed]
[32] Syu, A., Ishiguro, H., Inada, T., Horiuchi, Y., Tanaka, S., Ishikawa, M., et al. (2010) Association of the HSPG2 Gene with Neuroleptic-Induced Tardive Dyskinesia. Neuropsychopharmacology, 35, 1155-1164. [Google Scholar] [CrossRef] [PubMed]
[33] Lu, L., Bai, M., Zheng, Y., Wang, X., Chen, Z., Peng, R., et al. (2024) The Interaction of Endorepellin and Neurexin Triggers Neuroepithelial Autophagy and Maintains Neural Tube Development. Science Bulletin, 69, 2260-2272. [Google Scholar] [CrossRef] [PubMed]
[34] Zhang, W., Lin, Z., Shi, F., Wang, Q., Kong, Y., Ren, Y., et al. (2022) HSPG2 Mutation Association with Immune Checkpoint Inhibitor Outcome in Melanoma and Non-Small Cell Lung Cancer. Cancers, 14, Article No. 3495. [Google Scholar] [CrossRef] [PubMed]
[35] Zhou, X., Liang, S., Zhan, Q., Yang, L., Chi, J. and Wang, L. (2020) HSPG2 Overexpression Independently Predicts Poor Survival in Patients with Acute Myeloid Leukemia. Cell Death & Disease, 11, Article No. 492. [Google Scholar] [CrossRef] [PubMed]
[36] Li, C., Luo, P., Guo, F., Jia, X., Shen, M., Zhang, T., et al. (2024) Identification of HSPG2 as a Bladder Pro-Tumor Protein through NID1/AKT Signaling. Cancer Cell International, 24, Article No. 345. [Google Scholar] [CrossRef] [PubMed]
[37] Zhang, S., Guo, M., Guo, T., Yang, M., Cheng, J., Cui, C., et al. (2021) DAL-1/4.1B Promotes the Uptake of Exosomes in Lung Cancer Cells via Heparan Sulfate Proteoglycan 2 (HSPG2). Molecular and Cellular Biochemistry, 477, 241-254. [Google Scholar] [CrossRef] [PubMed]
[38] Kalscheuer, S., Khanna, V., Kim, H., Li, S., Sachdev, D., DeCarlo, A., et al. (2019) Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer. Scientific Reports, 9, Article No. 12492. [Google Scholar] [CrossRef] [PubMed]
[39] Ma, X.L., Shang, F., Ni, W., Zhu, J., Luo, B. and Zhang, Y.Q. (2018) Increased HSPG2 Expression Independently Predicts Poor Survival in Patients with Oligoastrocytoma and Oligodendroglioma. European Review for Medical and Pharmacological Sciences, 22, 6853-6863.
[40] Wang, X., Zuo, D., Chen, Y., Li, W., Liu, R., He, Y., et al. (2014) Shed Syndecan-1 Is Involved in Chemotherapy Resistance via the EGFR Pathway in Colorectal Cancer. British Journal of Cancer, 111, 1965-1976. [Google Scholar] [CrossRef] [PubMed]
[41] Kim, A.W., Xu, X., Hollinger, E.F., Gattuso, P., Godellas, C.V. and Prinz, R.A. (2002) Human Heparanase-1 Gene Expression in Pancreatic Adenocarcinoma. Journal of Gastrointestinal Surgery, 6, 167-172. [Google Scholar] [CrossRef] [PubMed]