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Gene Review

HPSE  -  heparanase

Homo sapiens

Synonyms: Endo-glucoronidase, HEP, HPA, HPA1, HPR1, ...
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Disease relevance of HPSE


Psychiatry related information on HPSE


High impact information on HPSE

  • Productive hand off correlated with local heparanase expression either from malignant tumor cells and/or as a result of T-cell activation by antigen, providing high levels of selectivity for viral transfer to metastatic tumors in vivo [12].
  • Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis [13].
  • Degradation of heparan sulfate by endoglycosidic heparanase cleavage affects a variety of biological processes [14].
  • The heparanase mRNA and protein are preferentially expressed in metastatic cell lines and specimens of human breast, colon and liver carcinomas [14].
  • Low metastatic murine T-lymphoma and melanoma cells transfected with the heparanase cDNA acquired a highly metastatic phenotype in vivo, reflected by a massive liver and lung colonization [14].

Chemical compound and disease context of HPSE


Biological context of HPSE

  • The tight regulation of HPSE expression and function is critical to ensure homeostasis of the normal physiological processes to which it contributes and to prevent imbalance toward pathological situations [1].
  • The HPSE 1a-form contains all 14 exons, whereas in the HPSE 1b-form the first and fourteenth exons (5'- and 3'-untranslated region) have been spliced out [2].
  • Studies using heparanase inhibitors and gene silencing have provided evidence to support an important role for heparanase in tumor metastasis and angiogenesis [3].
  • Cleavage of heparan sulfate by the beta-D-endoglucuronidase heparanase (HPSE) is a fundamental event in a number of important physiological processes including inflammation, wound healing, and angiogenesis [1].
  • Furthermore, the heparanase promoter region containing the EGR1 sites was also inducible in tumor cells and induction corresponded to HPSE expression levels [3].

Anatomical context of HPSE


Associations of HPSE with chemical compounds

  • COX-2 promoter was activated after heparanase cDNA was transduced and the deletion/mutation of three transcription factor (cyclic AMP response element, nuclear factor-kappaB, and nuclear factor-interleukin-6) binding elements in COX-2 promoter strongly suppressed its activity [22].
  • In addition, glomerular HPSE expression is upregulated in rats (messenger RNA (mRNA) 2.5-fold, protein three-fold) and mice (mRNA seven-fold, protein 1.5-fold) with STZ-induced diabetes [23].
  • Processing of macromolecular heparin by heparanase [24].
  • Induction of HPR1 expression by high glucose led to decreased cell surface heparan sulfate expression [17].
  • These findings strongly suggest that the intracellular processing of the heparin proteoglycan polysaccharide chains is catalyzed by heparanase, which primarily cleaves target structures distinct from the antithrombin-binding sequence [24].
  • The molecular mechanism of the estrogenlike effect of tamoxifen on heparanase expression involves recruitment of transcription coactivator AIB1 to the heparanase promoter [25].

Physical interactions of HPSE


Enzymatic interactions of HPSE


Co-localisations of HPSE

  • Inhibition of deaminative cleavage did not prevent heparanase from generating heparan sulfate oligosaccharides that colocalized strongly with caveolin-1 [32].

Regulatory relationships of HPSE


Other interactions of HPSE


Analytical, diagnostic and therapeutic context of HPSE

  • Functional dissection of the heparanase promoter identified a 280-bp region that was critical for transcription of the heparanase gene [3].
  • Human esophageal cancer cells were transduced with heparanase cDNA and used for reverse transcription-PCR and Western blot to determine the expression of heparanase and COX-2 [22].
  • Immunofluorescence staining was performed to analyze HS, HPSE, and agrin core protein expression in kidney biopsies from patients with overt DNP and from rats and mice with streptozotocin (STZ)-induced diabetes [23].
  • These studies describe a novel experimental animal model for examining the spontaneous metastasis of bone-homing tumors and indicate that heparanase is a critical determinant of myeloma dissemination and growth in vivo [38].
  • In addition, expression of heparanase by myeloma cells (1) accelerates the initial growth of the primary tumor, (2) increases whole-body tumor burden as compared with controls, and (3) enhances both the number and size of microvessels within the primary tumor [38].


  1. Regulation of inducible heparanase gene transcription in activated T cells by early growth response 1. de Mestre, A.M., Khachigian, L.M., Santiago, F.S., Staykova, M.A., Hulett, M.D. J. Biol. Chem. (2003) [Pubmed]
  2. Genomic organization and chromosome localization of the newly identified human heparanase gene. Dong, J., Kukula, A.K., Toyoshima, M., Nakajima, M. Gene (2000) [Pubmed]
  3. Early growth response gene 1 (EGR1) regulates heparanase gene transcription in tumor cells. de Mestre, A.M., Rao, S., Hornby, J.R., Soe-Htwe, T., Khachigian, L.M., Hulett, M.D. J. Biol. Chem. (2005) [Pubmed]
  4. Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer. Ogishima, T., Shiina, H., Breault, J.E., Terashima, M., Honda, S., Enokida, H., Urakami, S., Tokizane, T., Kawakami, T., Ribeiro-Filho, L.A., Fujime, M., Kane, C.J., Carroll, P.R., Igawa, M., Dahiya, R. Oncogene (2005) [Pubmed]
  5. Function of heparanase in prostate tumorigenesis: potential for therapy. Lerner, I., Baraz, L., Pikarsky, E., Meirovitz, A., Edovitsky, E., Peretz, T., Vlodavsky, I., Elkin, M. Clin. Cancer Res. (2008) [Pubmed]
  6. Expression of heparanase in renal cell carcinomas: implications for tumor invasion and prognosis. Mikami, S., Oya, M., Shimoda, M., Mizuno, R., Ishida, M., Kosaka, T., Mukai, M., Nakajima, M., Okada, Y. Clin. Cancer Res. (2008) [Pubmed]
  7. Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior. Zcharia, E., Metzger, S., Chajek-Shaul, T., Aingorn, H., Elkin, M., Friedmann, Y., Weinstein, T., Li, J.P., Lindahl, U., Vlodavsky, I. FASEB J. (2004) [Pubmed]
  8. Brain corticosteroid receptor balance in health and disease. De Kloet, E.R., Vreugdenhil, E., Oitzl, M.S., Joëls, M. Endocr. Rev. (1998) [Pubmed]
  9. The prognostic significance of HPA-axis disturbance in panic disorder: a three-year follow-up. Coryell, W., Noyes, R., Reich, J. Biol. Psychiatry (1991) [Pubmed]
  10. Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin. Akil, H., Haskett, R.F., Young, E.A., Grunhaus, L., Kotun, J., Weinberg, V., Greden, J., Watson, S.J. Biol. Psychiatry (1993) [Pubmed]
  11. Reduced skeletal muscle oxygen uptake and reduced beta-cell function: two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes. Thamer, C., Stumvoll, M., Niess, A., Tschritter, O., Haap, M., Becker, R., Shirkavand, F., Bachmann, O., Rett, K., Volk, A., Häring, H., Fritsche, A. Diabetes Care (2003) [Pubmed]
  12. Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells. Cole, C., Qiao, J., Kottke, T., Diaz, R.M., Ahmed, A., Sanchez-Perez, L., Brunn, G., Thompson, J., Chester, J., Vile, R.G. Nat. Med. (2005) [Pubmed]
  13. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Hulett, M.D., Freeman, C., Hamdorf, B.J., Baker, R.T., Harris, M.J., Parish, C.R. Nat. Med. (1999) [Pubmed]
  14. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Vlodavsky, I., Friedmann, Y., Elkin, M., Aingorn, H., Atzmon, R., Ishai-Michaeli, R., Bitan, M., Pappo, O., Peretz, T., Michal, I., Spector, L., Pecker, I. Nat. Med. (1999) [Pubmed]
  15. Cell surface expression and secretion of heparanase markedly promote tumor angiogenesis and metastasis. Goldshmidt, O., Zcharia, E., Abramovitch, R., Metzger, S., Aingorn, H., Friedmann, Y., Schirrmacher, V., Mitrani, E., Vlodavsky, I. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  16. Structural recognition by recombinant human heparanase that plays critical roles in tumor metastasis. Hierarchical sulfate groups with different effects and the essential target disulfated trisaccharide sequence. Okada, Y., Yamada, S., Toyoshima, M., Dong, J., Nakajima, M., Sugahara, K. J. Biol. Chem. (2002) [Pubmed]
  17. Heparanase-1 gene expression and regulation by high glucose in renal epithelial cells: a potential role in the pathogenesis of proteinuria in diabetic patients. Maxhimer, J.B., Somenek, M., Rao, G., Pesce, C.E., Baldwin, D., Gattuso, P., Schwartz, M.M., Lewis, E.J., Prinz, R.A., Xu, X. Diabetes (2005) [Pubmed]
  18. Substrate specificity of heparanases from human hepatoma and platelets. Pikas, D.S., Li, J.P., Vlodavsky, I., Lindahl, U. J. Biol. Chem. (1998) [Pubmed]
  19. Heparanase activity is dysregulated in children with steroid-sensitive nephrotic syndrome. Holt, R.C., Webb, N.J., Ralph, S., Davies, J., Short, C.D., Brenchley, P.E. Kidney Int. (2005) [Pubmed]
  20. Transfection of antisense oligodeoxynucleotide inhibits heparanase gene expression and invasive ability of human pancreatic cancer cell in vitro. Gao, J., Su, L., Qin, R., Chang, Q., Huang, T., Feng, Y. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban. (2006) [Pubmed]
  21. FGF2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells. Reiland, J., Kempf, D., Roy, M., Denkins, Y., Marchetti, D. Neoplasia (2006) [Pubmed]
  22. Heparanase is involved in angiogenesis in esophageal cancer through induction of cyclooxygenase-2. Okawa, T., Naomoto, Y., Nobuhisa, T., Takaoka, M., Motoki, T., Shirakawa, Y., Yamatsuji, T., Inoue, H., Ouchida, M., Gunduz, M., Nakajima, M., Tanaka, N. Clin. Cancer Res. (2005) [Pubmed]
  23. Increased expression of heparanase in overt diabetic nephropathy. van den Hoven, M.J., Rops, A.L., Bakker, M.A., Aten, J., Rutjes, N., Roestenberg, P., Goldschmeding, R., Zcharia, E., Vlodavsky, I., van der Vlag, J., Berden, J.H. Kidney Int. (2006) [Pubmed]
  24. Processing of macromolecular heparin by heparanase. Gong, F., Jemth, P., Escobar Galvis, M.L., Vlodavsky, I., Horner, A., Lindahl, U., Li, J.P. J. Biol. Chem. (2003) [Pubmed]
  25. Tamoxifen induces heparanase expression in estrogen receptor-positive breast cancer. Cohen, I., Maly, B., Simon, I., Meirovitz, A., Pikarsky, E., Zcharia, E., Peretz, T., Vlodavsky, I., Elkin, M. Clin. Cancer Res. (2007) [Pubmed]
  26. Increased heparanase expression is caused by promoter hypomethylation and up-regulation of transcriptional factor early growth response-1 in human prostate cancer. Ogishima, T., Shiina, H., Breault, J.E., Tabatabai, L., Bassett, W.W., Enokida, H., Li, L.C., Kawakami, T., Urakami, S., Ribeiro-Filho, L.A., Terashima, M., Fujime, M., Igawa, M., Dahiya, R. Clin. Cancer Res. (2005) [Pubmed]
  27. Human heparanase is localized within lysosomes in a stable form. Goldshmidt, O., Nadav, L., Aingorn, H., Irit, C., Feinstein, N., Ilan, N., Zamir, E., Geiger, B., Vlodavsky, I., Katz, B.Z. Exp. Cell Res. (2002) [Pubmed]
  28. Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia. Rosenthal, M.A., Rischin, D., McArthur, G., Ribbons, K., Chong, B., Fareed, J., Toner, G., Green, M.D., Basser, R.L. Ann. Oncol. (2002) [Pubmed]
  29. Heparanase and a synthetic peptide of heparan sulfate-interacting protein recognize common sites on cell surface and extracellular matrix heparan sulfate. Marchetti, D., Liu, S., Spohn, W.C., Carson, D.D. J. Biol. Chem. (1997) [Pubmed]
  30. Modulations of glypican-1 heparan sulfate structure by inhibition of endogenous polyamine synthesis. Mapping of spermine-binding sites and heparanase, heparin lyase, and nitric oxide/nitrite cleavage sites. Ding, K., Sandgren, S., Mani, K., Belting, M., Fransson, L.A. J. Biol. Chem. (2001) [Pubmed]
  31. Structure modeling, ligand binding, and binding affinity calculation (LR-MM-PBSA) of human heparanase for inhibition and drug design. Zhou, Z., Bates, M., Madura, J.D. Proteins (2006) [Pubmed]
  32. Nitric oxide-dependent processing of heparan sulfate in recycling S-nitrosylated glypican-1 takes place in caveolin-1-containing endosomes. Cheng, F., Mani, K., van den Born, J., Ding, K., Belting, M., Fransson, L.A. J. Biol. Chem. (2002) [Pubmed]
  33. Matrix metalloproteinase can facilitate the heparanase-induced promotion of phenotype change in vascular smooth muscle cells. Fitzgerald, M., Hayward, I.P., Thomas, A.C., Campbell, G.R., Campbell, J.H. Atherosclerosis (1999) [Pubmed]
  34. Correlation of overexpression of the low-affinity p75 neurotrophin receptor with augmented invasion and heparanase production in human malignant melanoma cells. Walch, E.T., Albino, A.P., Marchetti, D. Int. J. Cancer (1999) [Pubmed]
  35. Low incidence of paradoxical platelet activation by glycoprotein IIb/IIIa inhibitors. Weber, A.A., Meila, D., Jacobs, C., Weber, S., Kelm, M., Strauer, B.E., Zotz, R.B., Scharf, R.E., Schrör, K. Thromb. Res. (2002) [Pubmed]
  36. In Vivo and in Vitro Degradation of Heparan Sulfate (HS) Proteoglycans by HPR1 in Pancreatic Adenocarcinomas: LOSS OF CELL SURFACE HS SUPPRESSES FIBROBLAST GROWTH FACTOR 2-MEDIATED CELL SIGNALING AND PROLIFERATION. Xu, X., Rao, G., Quiros, R.M., Kim, A.W., Miao, H.Q., Brunn, G.J., Platt, J.L., Gattuso, P., Prinz, R.A. J. Biol. Chem. (2007) [Pubmed]
  37. Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells. Eshel, R., Ben-Zaken, O., Vainas, O., Nadir, Y., Minucci, S., Polliack, A., Naparstek, E., Vlodavsky, I., Katz, B.Z. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  38. Heparanase promotes the spontaneous metastasis of myeloma cells to bone. Yang, Y., Macleod, V., Bendre, M., Huang, Y., Theus, A.M., Miao, H.Q., Kussie, P., Yaccoby, S., Epstein, J., Suva, L.J., Kelly, T., Sanderson, R.D. Blood (2005) [Pubmed]
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