TISIDB

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Lysosome membrane; Peripheral membrane protein. Secreted. Nucleus. Note=Proheparanase is secreted via vesicles of the Golgi. Interacts with cell membrane heparan sulfate proteoglycans (HSPGs). Endocytosed and accumulates in endosomes. Transferred to lysosomes where it is proteolytically cleaved to produce the active enzyme. Under certain stimuli, transferred to the cell surface. Associates with lipid rafts. Colocalizes with SDC1 in endosomal/lysosomal vesicles. Accumulates in perinuclear lysosomal vesicles. Heparin retains proheparanase in the extracellular medium (By similarity).
Domain	PF03662 Glycosyl hydrolase family 79
Function	Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extracellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis.

> Gene Ontology [ TOP ]
Biological Process	GO:0001525 angiogenesis GO:0001819 positive regulation of cytokine production GO:0001942 hair follicle development GO:0006022 aminoglycan metabolic process GO:0006026 aminoglycan catabolic process GO:0006027 glycosaminoglycan catabolic process GO:0006029 proteoglycan metabolic process GO:0006516 glycoprotein catabolic process GO:0006790 sulfur compound metabolic process GO:0007160 cell-matrix adhesion GO:0007596 blood coagulation GO:0007599 hemostasis GO:0008544 epidermis development GO:0009100 glycoprotein metabolic process GO:0010573 vascular endothelial growth factor production GO:0010574 regulation of vascular endothelial growth factor production GO:0010575 positive regulation of vascular endothelial growth factor production GO:0022404 molting cycle process GO:0022405 hair cycle process GO:0030167 proteoglycan catabolic process GO:0030193 regulation of blood coagulation GO:0030194 positive regulation of blood coagulation GO:0030198 extracellular matrix organization GO:0030200 heparan sulfate proteoglycan catabolic process GO:0030201 heparan sulfate proteoglycan metabolic process GO:0030203 glycosaminoglycan metabolic process GO:0031589 cell-substrate adhesion GO:0033687 osteoblast proliferation GO:0033688 regulation of osteoblast proliferation GO:0033690 positive regulation of osteoblast proliferation GO:0042303 molting cycle GO:0042633 hair cycle GO:0042634 regulation of hair cycle GO:0042635 positive regulation of hair cycle GO:0043062 extracellular structure organization GO:0043491 protein kinase B signaling GO:0043588 skin development GO:0044273 sulfur compound catabolic process GO:0045682 regulation of epidermis development GO:0045684 positive regulation of epidermis development GO:0048514 blood vessel morphogenesis GO:0050817 coagulation GO:0050818 regulation of coagulation GO:0050820 positive regulation of coagulation GO:0050878 regulation of body fluid levels GO:0051797 regulation of hair follicle development GO:0051798 positive regulation of hair follicle development GO:0051896 regulation of protein kinase B signaling GO:0051897 positive regulation of protein kinase B signaling GO:0060055 angiogenesis involved in wound healing GO:0061041 regulation of wound healing GO:0061042 vascular wound healing GO:0090303 positive regulation of wound healing GO:0098773 skin epidermis development GO:1900046 regulation of hemostasis GO:1900048 positive regulation of hemostasis GO:1901136 carbohydrate derivative catabolic process GO:1901565 organonitrogen compound catabolic process GO:1903034 regulation of response to wounding GO:1903036 positive regulation of response to wounding
Molecular Function	GO:0001948 glycoprotein binding GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds GO:0004566 beta-glucuronidase activity GO:0016798 hydrolase activity, acting on glycosyl bonds GO:0030305 heparanase activity GO:0043394 proteoglycan binding GO:0043395 heparan sulfate proteoglycan binding GO:0045545 syndecan binding GO:1901681 sulfur compound binding
Cellular Component	GO:0005578 proteinaceous extracellular matrix GO:0005765 lysosomal membrane GO:0005775 vacuolar lumen GO:0043202 lysosomal lumen GO:0045121 membrane raft GO:0098589 membrane region GO:0098852 lytic vacuole membrane GO:0098857 membrane microdomain

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa00531 Glycosaminoglycan degradation hsa01100 Metabolic pathways
Reactome	R-HSA-1630316: Glycosaminoglycan metabolism R-HSA-2024096: HS-GAG degradation R-HSA-1638091: Heparan sulfate/heparin (HS-GAG) metabolism R-HSA-168256: Immune System R-HSA-168249: Innate Immune System R-HSA-1430728: Metabolism R-HSA-71387: Metabolism of carbohydrates R-HSA-6798695: Neutrophil degranulation

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between HPSE and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between HPSE and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
25849134	Breast Carcinoma; Neuroblastoma	Promote immunity (T cell function; infiltration)	Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes.
18316618	Melanoma; Lymphoma; Lung Carcinoma	Promote immunity (T cell function); essential for immunotherapy	H-2Kb-restricted CTL epitopes from mouse heparanase elicit an antitumor immune response in vivo.
28581441	Melanoma; Prostate Carcinoma; Breast Carcinoma	Promote immunity (infiltration)	However, mice lacking heparanase specifically in NK cells (Hpsefl/fl NKp46-iCre mice) were highly tumor prone when challenged with the carcinogen methylcholanthrene (MCA). Cytokine and immune checkpoint blockade immunotherapy for metastases was compromised when NK cells lacked heparanase. NK cell invasion of primary tumors and recruitment to the site of metastasis were strictly dependent on the presence of heparanase.

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of HPSE in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of HPSE in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0.002	0.997
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.296	0.762
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.229	0.734
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0.379	0.307
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.241	0.818
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0.558	0.671
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.191	0.638
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.533	0.614
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.254	0.838
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	1.221	0.0915
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	1.072	0.37
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.172	0.313

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of HPSE in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	0	2.7	-2.7	1
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	0	3.4	-3.4	1
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	11.8	-7	0.577
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	12.5	16.7	-4.2	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	9.1	-9.1	0.458
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	11.1	0	11.1	0.36
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	20	0	20	0.357
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	0	5.3	0.507
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	0	6.2	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of HPSE. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of HPSE. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by HPSE. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of HPSE. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of HPSE expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between HPSE and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	HPSE
Name	heparanase
Aliases	HPA; HSE1; HPSE1; HPA1; HPR11; endo-glucoronidase; heparanase-1
Chromosomal Location	4q21.3
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting HPSE collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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