Heparanase-A single protein with multiple enzymatic and nonenzymatic functions.
heparan sulfate
heparanase
heparanase 2
signal transduction
Journal
Proteoglycan research
ISSN: 2832-3556
Titre abrégé: Proteoglycan Res
Pays: United States
ID NLM: 9918589889006676
Informations de publication
Date de publication:
01 Jul 2023
01 Jul 2023
Historique:
received:
18
04
2023
revised:
15
06
2023
accepted:
16
06
2023
medline:
7
8
2023
pubmed:
7
8
2023
entrez:
7
8
2023
Statut:
ppublish
Résumé
Heparanase (Hpa1) is expressed by tumor cells and cells of the tumor microenvironment and functions extracellularly to remodel the extracellular matrix (ECM) and regulate the bioavailability of ECM-bound factors, augmenting, among other effects, gene transcription, autophagy, exosome formation, and heparan sulfate (HS) turnover. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis, and chemoresistance. The enzyme appears to fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, autophagy, HS turnover, and gene transcription. It activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and nonenzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive tumor growth, dissemination, and drug resistance as well as inflammatory responses. The emerging premise is that heparanase expressed by tumor cells, immune cells, endothelial cells, and other cells of the tumor microenvironment is a key regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a valid target for therapy. So far, however, antiheparanase-based therapy has not been implemented in the clinic. Unlike heparanase, heparanase-2 (Hpa2), a close homolog of heparanase (Hpa1), does not undergo proteolytic processing and hence lacks intrinsic HS-degrading activity, the hallmark of heparanase. Hpa2 retains the capacity to bind heparin/HS and exhibits an even higher affinity towards HS than heparanase, thus competing for HS binding and inhibiting heparanase enzymatic activity. It appears that Hpa2 functions as a natural inhibitor of Hpa1 regulates the expression of selected genes that maintain tissue hemostasis and normal function, and plays a protective role against cancer and inflammation, together emphasizing the significance of maintaining a proper balance between Hpa1 and Hpa2.
Identifiants
pubmed: 37547889
doi: 10.1002/pgr2.6
pii: PGR26
pmc: PMC10398610
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
e6Informations de copyright
© 2023 The Authors. Proteoglycan Research published by Wiley Periodicals LLC.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest
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