Alternative titles; symbols
HGNC Approved Gene Symbol: HPSE
Cytogenetic location: 4q21.23 Genomic coordinates (GRCh38) : 4:83,292,461-83,335,153 (from NCBI)
Heparan sulfate proteoglycans (HSPGs) are major components of the basement membrane and extracellular matrix. Heparanases, like HSPE, are endoglycosidases that cleave the heparan sulfate side chain of HSPGs to permit the remodeling of the extracellular matrix for cell movement or the release of bioactive molecules from the extracellular matrix or cell surface (summary by McKenzie et al., 2000).
By sequential affinity chromatography of SV40-transformed embryonic lung fibroblasts, Toyoshima and Nakajima (1999) purified a 50-kD protein with heparanase activity. Hulett et al. (1999) and Vlodavsky et al. (1999) applied similar strategies to platelets and placenta, respectively. By searching EST databases, all 3 groups identified cDNAs encoding a 543-amino acid heparanase protein (HPSE) with 6 potential N-glycosylation sites. The protein also has putative hydrophobic stretches suggestive of signal peptides and a transmembrane protein (Hulett et al., 1999). Northern blot analysis revealed expression of a 2-kb transcript in placenta, but not in heart, brain, lung, liver, skeletal muscle, kidney, or pancreas. A 4.4-kb transcript was expressed at low levels in all tissues. Both transcripts were expressed equivalently in peripheral blood leukocytes, spleen, lymph node, bone marrow, fetal liver, and thymus (Hulett et al., 1999; Kussie et al., 1999).
Using real-time quantitative RT-PCR, McKenzie et al. (2000) detected highest HPA1 expression in placenta and lymph node. In brain subregions, highest HPA1 expression was detected in corpus callosum. Expression of HPA1 was elevated in all tumor xenograft samples compared with the corresponding normal tissues. McKenzie et al. (2000) noted that the pattern of HPA2 (HPSE2; 613469) expression differed from that of HPA1 in both normal and tumor tissues.
Functional analyses by Toyoshima and Nakajima (1999), Hulett et al. (1999), and Vlodavsky et al. (1999) revealed that HPSE expression correlated with heparanase activity. Using RT-PCR, in situ hybridization, and functional analyses, Vlodavsky et al. (1999) demonstrated a correlation of HPSE expression and heparanase activity with increased metastatic potential in breast cancer tissues and cell lines.
Zhang et al. (2011) noted that elevated HPSE signaling has been implicated in brain metastatic breast cancer (BMBC). They identified a microRNA (miRNA) target sequence in the 3-prime UTR of the heparanase transcript that matched the seed sequence of miRNA1258 (MIR1258; 614488). MIR1258 expression was downregulated in BMBC cell lines compared with nonmetastatic or nontumorigenic mammary epithelial cells and in invasive ductal carcinoma and BMBC tissues compared with corresponding normal and primary tissues, respectively. In all cases, MIR1258 expression correlated negatively with HPSE expression. Overexpression of MIR1258 in cultured BMBC cells reduced phosphorylation of AKT (164730) and EGFR (131550), which are downstream markers in the HPSE signaling cascade. Stable MIR1258 expression in BMBC cells reduced their invasive phenotype in culture and reduced the metastatic potential of xenografts in mice.
Qu et al. (2015) identified a target site for MIR558 (616473) in the HPSE promoter region and found that MIR558 bound directly to the target sequence. Rather than inhibiting HPSE expression, MIR558 enhanced HPSE promoter activity. MIR558-induced HPSE expression increased neuroblastoma growth, invasion, metastasis, and angiogenesis.
Hulett et al. (1999) and Vlodavsky et al. (1999) determined that HPSE is a single-copy gene that contains 12 exons.
By fluorescence in situ hybridization and radiation hybrid analysis, Baker et al. (1999) mapped the HPSE gene to chromosome 4q21.3.
Baker, E., Crawford, J., Sutherland, G. R., Freeman, C., Parish, C. R., Hulett, M. D. Human HPA endoglycosidase heparanase. Chromosome Res. 7: 319 only, 1999. [PubMed: 10461877] [Full Text: https://doi.org/10.1023/a:1009235132576]
Hulett, M. D., Freeman, C., Hamdorf, B. J., Baker, R. T., Harris, M. J., Parish, C. R. Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis. Nature Med. 5: 803-809, 1999. [PubMed: 10395326] [Full Text: https://doi.org/10.1038/10525]
Kussie, P. H., Hulmes, J. D., Ludwig, D. L., Patel, S., Navarro, E. C., Seddon, A. P., Giorgio, N. A., Bohlen, P. Cloning and functional expression of a human heparanase gene. Biochem. Biophys. Res. Commun. 261: 183-187, 1999. [PubMed: 10405343] [Full Text: https://doi.org/10.1006/bbrc.1999.0962]
McKenzie, E., Tyson, K., Stamps, A., Smith, P., Turner, P., Barry, R., Hircock, M., Patel, S., Barry, E., Stubberfield, C., Terrett, J., Page, M. Cloning and expression profiling of Hpa2, a novel mammalian heparanase family member. Biochem. Biophys. Res. Commun. 276: 1170-1177, 2000. [PubMed: 11027606] [Full Text: https://doi.org/10.1006/bbrc.2000.3586]
Qu, H., Zheng, L., Pu, J., Mei, H., Xiang, X., Zhao, X., Li, D., Li, S., Mao, L., Huang, K., Tong, Q. miRNA-558 promotes tumorigenesis and aggressiveness of neuroblastoma cells through activating the transcription of heparanase. Hum. Molec. Genet. 24: 2539-2551, 2015. [PubMed: 25616966] [Full Text: https://doi.org/10.1093/hmg/ddv018]
Toyoshima, M., Nakajima, M. Human heparanase: purification, characterization, cloning, and expression. J. Biol. Chem. 274: 24153-24160, 1999. [PubMed: 10446189] [Full Text: https://doi.org/10.1074/jbc.274.34.24153]
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. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nature Med. 5: 793-802, 1999. [PubMed: 10395325] [Full Text: https://doi.org/10.1038/10518]
Zhang, L., Sullivan, P. S., Goodman, J. C., Gunaratne, P. H., Marchetti, D. MicroRNA-1258 suppresses breast cancer brain metastasis by targeting heparanase. Cancer Res. 71: 645-654, 2011. [PubMed: 21266359] [Full Text: https://doi.org/10.1158/0008-5472.CAN-10-1910]