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Gene Review

HPSE  -  heparanase

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Disease relevance of HPSE

  • Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase [1].
  • Heparanase, overexpressed by most cancer cells, facilitates extravasation of blood-borne tumor cells and causes release of growth factors sequestered by HS chains, thus accelerating tumor growth and metastasis [2].
  • On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase, inhibited at concentrations of 1 and 3 micrograms/ml, respectively [3].
  • A-72363 A-1, A-2, and C, novel heparanase inhibitors from Streptomyces nobilis SANK 60192, II. Biological activities [4].
  • Heparanase activity correlates with metastatic potentials of lymphoma, melanoma and mammary adenocarcinoma cell lines [5].

High impact information on HPSE


Chemical compound and disease context of HPSE

  • B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage heparanase [3].
  • Heparanase, an endo-beta-D-glucuronidase initially detected in B16 melanoma cells, has been described as a M(r) 96,000 glycoprotein with pI of 5.2, and has been immunolocalized to the cell surface and cytoplasm [9].

Biological context of HPSE


Anatomical context of HPSE

  • Furthermore, heparanase mRNA was detected in the cotyledon, intercotyledonary fetal membrane and caruncle after days 60-64 of gestation [10].
  • However, no significant expression of heparanase mRNA was observed in intercaruncular endometrium at all stages of gestation examined [10].
  • We hypothesize that decreased vessel wall HSPG, as occurs in atherogenic conditions, allows increased monocyte retention within the vessel and is due to the actions of an endothelial heparanase [12].
  • Our data suggests that the non-reducing end of bovine kidney heparan sulfate is not trimmed by heparanase and is capable of supporting fibroblast growth factor signaling complex formation [13].
  • Cell lysates of T lymphocytes contained heparanase activity [14].

Associations of HPSE with chemical compounds

  • The growth factor appears to be bound to heparan sulfate and is released from the cornea by treatment with heparin, a hexasaccharide heparin fragment, heparan sulfate, or heparanase, but not by chondroitin sulfate or chondroitinase [15].
  • Indeed N-acetylated heparins in their glycol-split forms inhibited heparanase as effectively as the corresponding N-sulfated derivatives [2].
  • Since 3H-reduced terminal monosaccharides from HS fragments were overwhelmingly (greater than 90%) L-gulonic acid, the HS-degrading enzyme responsible is an endoglucuronidase (heparanase) [1].
  • Whereas heparin and N-acetylheparins containing unmodified D-glucuronic acid residues inhibited heparanase by acting, at least in part, as substrates, their glycol-split derivatives were no more susceptible to cleavage by heparanase [2].
  • Trichostatin A abolished the inhibitory effect of wt p53, suggesting the involvement of histone deacetylation in negative regulation of the heparanase promoter [16].

Analytical, diagnostic and therapeutic context of HPSE

  • Quantitative real-time RT-PCR analysis showed very low expression of heparanase mRNA in the conceptus before implantation (day 17), but high expression in the cotyledon-containing fetal membrane (days 27-34) after implantation [10].
  • Western blot analysis of bovine placental extracts (day 60) was performed using anti-bovine HPA antibody prepared by immunization of rabbits with synthetic peptide conjugate corresponding to amino acid residues 474-489 of bovine HPA; it showed two immunoreactive proteins with approximate molecular weights of 55kDa and 65kDa [17].
  • In placentomes of 60 and 210 days' gestation, in situ hybridization demonstrated HPA mRNA expression in binucleate cells [17].


  1. Metastatic melanoma cell heparanase. Characterization of heparan sulfate degradation fragments produced by B16 melanoma endoglucuronidase. Nakajima, M., Irimura, T., Di Ferrante, N., Nicolson, G.L. J. Biol. Chem. (1984) [Pubmed]
  2. Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded N-acetylation, and glycol splitting. Naggi, A., Casu, B., Perez, M., Torri, G., Cassinelli, G., Penco, S., Pisano, C., Giannini, G., Ishai-Michaeli, R., Vlodavsky, I. J. Biol. Chem. (2005) [Pubmed]
  3. Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells. Savion, N., Disatnik, M.H., Nevo, Z. J. Cell. Physiol. (1987) [Pubmed]
  4. A-72363 A-1, A-2, and C, novel heparanase inhibitors from Streptomyces nobilis SANK 60192, II. Biological activities. Kawase, Y., Takahashi, M., Takatsu, T., Arai, M., Nakajima, M., Tanzawa, K. J. Antibiot. (1996) [Pubmed]
  5. Structural requirements for inhibition of melanoma lung colonization by heparanase inhibiting species of heparin. Bitan, M., Mohsen, M., Levi, E., Wygoda, M.R., Miao, H.Q., Lider, O., Svahn, C.M., Ekre, H.P., Ishai-Michaeli, R., Bar-Shavit, R. Isr. J. Med. Sci. (1995) [Pubmed]
  6. Subendothelial retention of lipoprotein (a). Evidence that reduced heparan sulfate promotes lipoprotein binding to subendothelial matrix. Pillarisetti, S., Paka, L., Obunike, J.C., Berglund, L., Goldberg, I.J. J. Clin. Invest. (1997) [Pubmed]
  7. A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparanase. Lider, O., Cahalon, L., Gilat, D., Hershkoviz, R., Siegel, D., Margalit, R., Shoseyov, O., Cohen, I.R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  8. Translocation of active heparanase to cell surface regulates degradation of extracellular matrix heparan sulfate upon transmigration of mature monocyte-derived dendritic cells. Benhamron, S., Nechushtan, H., Verbovetski, I., Krispin, A., Abboud-Jarrous, G., Zcharia, E., Edovitsky, E., Nahari, E., Peretz, T., Vlodavsky, I., Mevorach, D. J. Immunol. (2006) [Pubmed]
  9. Immunoselection of GRP94/endoplasmin from a KNRK cell-specific lambda gt11 library using antibodies directed against a putative heparanase amino-terminal peptide. De Vouge, M.W., Yamazaki, A., Bennett, S.A., Chen, J.H., Shwed, P.S., Couture, C., Birnboim, H.C. Int. J. Cancer (1994) [Pubmed]
  10. Expression of heparanase mRNA in bovine placenta during gestation. Kizaki, K., Nakano, H., Nakano, H., Takahashi, T., Imai, K., Hashizume, K. Reproduction (2001) [Pubmed]
  11. Structure-activity relationships of heparin-mimicking compounds in induction of bFGF release from extracellular matrix and inhibition of smooth muscle cell proliferation and heparanase activity. Benezra, M., Ishai-Michaeli, R., Ben-Sasson, S.A., Vlodavsky, I. J. Cell. Physiol. (2002) [Pubmed]
  12. Lysolecithin-induced alteration of subendothelial heparan sulfate proteoglycans increases monocyte binding to matrix. Sivaram, P., Obunike, J.C., Goldberg, I.J. J. Biol. Chem. (1995) [Pubmed]
  13. Characterizing the non-reducing end structure of heparan sulfate. Wu, Z.L., Lech, M. J. Biol. Chem. (2005) [Pubmed]
  14. Soluble antigen induces T lymphocytes to secrete an endoglycosidase that degrades the heparan sulfate moiety of subendothelial extracellular matrix. Fridman, R., Lider, O., Naparstek, Y., Fuks, Z., Vlodavsky, I., Cohen, I.R. J. Cell. Physiol. (1987) [Pubmed]
  15. A heparin-binding angiogenic protein--basic fibroblast growth factor--is stored within basement membrane. Folkman, J., Klagsbrun, M., Sasse, J., Wadzinski, M., Ingber, D., Vlodavsky, I. Am. J. Pathol. (1988) [Pubmed]
  16. Tumor suppressor p53 regulates heparanase gene expression. Baraz, L., Haupt, Y., Elkin, M., Peretz, T., Vlodavsky, I. Oncogene (2006) [Pubmed]
  17. Cloning and localization of heparanase in bovine placenta. Kizaki, K., Yamada, O., Nakano, H., Takahashi, T., Yamauchi, N., Imai, K., Hashizume, K. Placenta (2003) [Pubmed]
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