HPSE Gene: Heparanase - Function, Pathology, and Clinical Significance
A comprehensive overview of the HPSE gene, its protein product heparanase, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | HPSE |
|---|---|
| Full Name | Heparanase |
| Gene Type | Protein coding |
| Chromosomal Location | 4q21.3 |
| NCBI Gene ID | 10855 ncbi.nlm.nih.gov/gene/10855 |
| Ensembl ID | ENSG00000135114 |
| UniProt ID | Q9Y251 |
| OMIM ID | 604724 |
| HGNC ID | 5163 |
| Aliases | HPA, HPSE1, HPA1 |
Description
The HPSE gene encodes the enzyme heparanase, an endo-beta-D-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans (HSPGs). This cleavage activity is a critical step in the remodeling of the extracellular matrix (ECM) and basement membrane. By degrading HS, heparanase facilitates cell migration, invasion, and the release of HS-bound growth factors, cytokines, and enzymes. This activity is fundamental to various physiological and pathological processes, including embryonic development, wound healing, inflammation, and notably, cancer progression and metastasis. The protein is synthesized as a latent 65 kDa precursor that is processed to an active heterodimer. HPSE is also implicated in the regulation of gene expression and signaling pathways independent of its enzymatic activity.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | HPSE overexpression promotes tumor invasion, metastasis, and angiogenesis by degrading the ECM and releasing pro-angiogenic factors like VEGF and bFGF. It also contributes to an immunosuppressive tumor microenvironment. | High HPSE expression correlates with poor prognosis and increased metastatic potential in numerous cancers, including breast, lung, colon, gastric, and pancreatic cancers. Evidence from numerous studies and reviews on NCBI/PubMed. |
| Inflammatory Diseases | HPSE activity facilitates leukocyte extravasation from the bloodstream into tissues by degrading the endothelial basement membrane. It also promotes the release of pro-inflammatory cytokines and chemokines. | Elevated HPSE expression is observed in inflammatory conditions such as inflammatory bowel disease (IBD), rheumatoid arthritis, and atherosclerosis. Studies show that HPSE inhibitors can reduce inflammation in animal models. |
| Diabetic Nephropathy | HPSE-mediated degradation of HS in the glomerular basement membrane (GBM) leads to increased proteinuria, a hallmark of diabetic nephropathy. Loss of HS disrupts the charge-selective filtration barrier of the kidney. | Increased HPSE expression and activity are found in the kidneys of diabetic patients and animal models. This is associated with albuminuria and progression of renal damage. |
| Atherosclerosis | HPSE contributes to the progression of atherosclerotic plaques by promoting smooth muscle cell migration, inflammation, and intraplaque angiogenesis. | HPSE expression is upregulated in atherosclerotic lesions, particularly in macrophages and endothelial cells. It is linked to plaque instability and rupture. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Spleen | 35.1 | Medium |
| Lymph Node | 25.3 | Medium |
| Bone Marrow | 22.8 | Medium |
| Placenta | 20.4 | Medium |
| Lung | 15.2 | Low |
| Liver | 10.1 | Low |
| Kidney | 9.8 | Low |
| Brain | 2.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| THP-1 (Monocyte) | 45.2 | High expression in monocytic leukemia cell line. |
| A549 (Lung Carcinoma) | 18.5 | Moderate expression in lung cancer cell line. |
| MCF7 (Breast Carcinoma) | 12.3 | Low to moderate expression in breast cancer cell line. |
| HepG2 (Hepatocellular Carcinoma) | 8.7 | Low expression in liver cancer cell line. |
| K-562 (Chronic Myelogenous Leukemia) | 5.4 | Low expression in leukemia cell line. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| rs4693608 | SNV (Intronic) | Common (MAF ~0.3) | Associated with altered HPSE expression levels in some populations, potentially influencing disease susceptibility. |
| rs4364254 | SNV (Intronic) | Common (MAF ~0.4) | Linked to variations in HPSE expression and activity, studied in context of diabetic nephropathy and cancer. |
| c.1298C>T (p.Pro433Leu) | Missense | Rare | A rare variant that may affect protein stability or enzymatic activity, though clinical significance is not fully established. |
| c.1120G>A (p.Val374Ile) | Missense | Rare | Another rare missense variant with unknown functional consequence, reported in population databases. |
Mutation functional classification
Loss of Function (LOF)
Complete loss-of-function mutations in HPSE are rare and not well-documented in human populations. However, studies in animal models suggest that a complete knockout is viable but leads to altered ECM structure, reduced inflammation, and impaired tumor progression. In humans, no clear pathogenic loss-of-function variants have been established, suggesting that a complete absence of HPSE activity may be incompatible with normal development or is highly selected against.
Gain of Function (GOF)
Gain-of-function is primarily achieved through transcriptional upregulation rather than activating mutations. Overexpression of the wild-type protein is a common feature in aggressive cancers and inflammatory diseases. No specific activating mutations that increase the intrinsic enzymatic activity of the protein have been conclusively identified in the literature.
Dominant Negative (DN)
No dominant-negative mutations have been described for HPSE. The protein functions as a heterodimer, and it is theoretically possible that a mutation in one allele could produce a non-functional subunit that interferes with the active dimer. However, no such naturally occurring or experimentally created dominant-negative variant has been reported in the literature.
View complete mutation data：
Gene Ontology (GO)
| • heparan sulfate proteoglycan binding | • heparanase activity |
| • hydrolase activity | • acting on glycosyl bonds |
| • extracellular matrix organization | • heparan sulfate proteoglycan catabolic process |
| • angiogenesis | • cell migration |
| • inflammatory response | • extracellular space |
| • extracellular matrix |
Pathways
• Degradation of the extracellular matrix
• Heparan sulfate/heparin metabolism
• VEGF signaling pathway (via release of VEGF)
• FGF signaling pathway (via release of bFGF)
• Integrin signaling pathway (via ECM remodeling)
Protein Summary
Heparanase is a 65 kDa endo-beta-D-glucuronidase that is synthesized as a latent pro-enzyme and proteolytically processed into a 50 kDa and 8 kDa heterodimer to become active. It is the primary enzyme in mammals capable of cleaving heparan sulfate (HS) side chains on proteoglycans. This cleavage activity is central to its role in remodeling the extracellular matrix (ECM) and basement membrane. By degrading HS, heparanase facilitates cell invasion and migration, and releases HS-bound bioactive molecules such as growth factors (e.g., VEGF, bFGF), chemokines, and cytokines. Beyond its enzymatic function, heparanase also has non-enzymatic roles, including regulation of gene expression and cell signaling, which contribute to its effects on inflammation, angiogenesis, and cancer progression. Its expression is tightly regulated and is generally low in normal adult tissues but is significantly upregulated in various pathological conditions, particularly in tumors and inflamed tissues.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HPSE Knockout HEK293 Cell Line | EDJ-KQ2346 | Human | 10855 | Details Get a Quote |
| HPSE2 Knockout HEK293 Cell Line | EDJ-KQ13775 | Human | 60495 | Details Get a Quote |
| HPSE Knockout A-549 Cell Line | EDJ-KQ22770 | Human | 10855 | Details Get a Quote |
| HPSE Knockout HCT 116 Cell Line | EDJ-KQ22771 | Human | 10855 | Details Get a Quote |
| HPSE Knockout HeLa Cell Line | EDJ-KQ22772 | Human | 10855 | Details Get a Quote |
| HPSE2 Knockout HeLa Cell Line | EDJ-KQ56982 | Human | 60495 | Details Get a Quote |
| HPSE2 Knockout A-549 Cell Line | EDJ-KQ65484 | Human | 60495 | Details Get a Quote |
| HPSE2 Knockout HCT 116 Cell Line | EDJ-KQ73922 | Human | 60495 | Details Get a Quote |
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