Heparanase Plays a Dual Role in Driving Hepatocyte Growth Factor (HGF) Signaling by Enhancing HGF Expression and Activity

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-2182, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 02/2011; 286(8):6490-9. DOI: 10.1074/jbc.M110.183277
Source: PubMed


Hepatocyte growth factor (HGF) is a heparin-binding cytokine that enhances growth, motility, and angiogenesis of many tumor types, including multiple myeloma where it is often highly expressed. However, little is known regarding what controls HGF level and activity in these tumors. Evaluation of bone marrow biopsies from myeloma patients revealed a strong positive correlation between the levels of HGF and heparanase, an endoglucuronidase known to promote aggressive tumor behavior. In vitro, addition of recombinant heparanase to myeloma cells or transfection of myeloma cell lines with the cDNA for heparanase significantly increased tumor cell expression and secretion of biologically active HGF. Shed syndecan-1, whose levels in myeloma are also enhanced by heparanase expression, binds to secreted HGF. This syndecan-1-HGF complex is active as shown by its ability to stimulate paracrine signaling via c-Met, the cell surface receptor for HGF. Surprisingly, heparanase enzyme activity was not required for up-regulation of HGF expression by the tumor cells. This is in contrast to the heparanase-mediated enhanced syndecan-1 shedding, which does require activity of the enzyme. This suggests that two different functional domains within the heparanase enzyme (the enzyme active site and a separate site) contribute to events leading to enhanced HGF signaling. These findings demonstrate a novel mechanism driving the HGF pathway whereby heparanase stimulates an increase in both HGF expression and syndecan-1 shedding to enhance HGF signaling. This work also provides further mechanistic insight into the dynamic role of heparanase in driving aggressive tumor progression.

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Available from: Yang Yang, May 20, 2015
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    • "These effects are mediated not only from the high phosphorylation of ERK, but also due to the diminished levels of SDC-1 in the nucleus, leading to increased levels of acetylated histone H3 and eventually facilitating the transcription of VEGF and MMP-9 (100). As a result, MMP-9 cleaves SDC-1 from the cell surface and therefore interacts with growth factors like hepatocyte growth factor (HGF) and VEGF, whose expression is already stimulated by heparanase (134). Then, the “loaded” with growth factors shed SDC-1 binds to ECM macromolecules, such as FN and collagen, rendering these growth factors available in the tumor microenvironment even in distal sites. "
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    ABSTRACT: Extracellular matrix (ECM) components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs). Specifically, heparan sulfate (HS) chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases, ADAM as well as ADAMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble SDCs "shed SDCs" in the ECM interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed SDCs, upon binding to several matrix effectors, such as growth factors, chemokines, and cytokines, have the ability to act as competitive inhibitors for membrane proteoglycans, and modulate the inflammatory microenvironment of cancer cells. It is notable that SDCs and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of SDCs in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma.
    Frontiers in Oncology 02/2014; 4:4. DOI:10.3389/fonc.2014.00004
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    • "Heparanase exhibits also non-enzymatic activities, independent of its involvement in ECM degradation. It includes enhanced adhesion of various cancer cells [10], [11], enhanced Akt signaling and stimulation of PI3K- and p38-dependent endothelial cell migration [12], [13], Src mediated phosphorylation of the EGF receptor [14], phosphorylation of STAT [15], activation of TLR2 and 4 [16], and up regulation of VEGF [13] and HGF [17], all contributing to its potent pro-tumorigenic and pro-inflammatory activities [5]. The molecular mechanism by which heparanase elicits signal transduction has not been resolved but is thought to involve the heparanase C-terminus domain [18] and various heparanase binding protein(s)/receptor(s) [18]–[20]. "
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    ABSTRACT: In an attempt to isolate a heparanase receptor, postulated to mediate non-enzymatic functions of the heparanase protein, we utilized human urine collected from healthy volunteers. Affinity chromatography of this rich protein source on immobilized heparanase revealed resistin as a heparanase binding protein. Co-immunoprecipitation and ELISA further confirmed the interaction between heparanase and resistin. Importantly, we found that heparanase potentiates the bioactivity of resistin in its standard bioassay in which monocytic human leukemia cell line, THP1, differentiates into adherent macrophage-like foam cells. It is thus conceivable that this newly identified complex of heparanase and resistin exerts a stimulatory effect also in various inflammatory conditions known to be affected by the two proteins.
    PLoS ONE 01/2014; 9(1):e85944. DOI:10.1371/journal.pone.0085944 · 3.23 Impact Factor
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    • "Interaction of Hpse with cell surface receptors on endothelial cells activates intracellular Akt, PI3K, and p38 kinase signaling to stimulate cell migration and Src kinase-mediated upregulation of vascular endothelial growth factor (VEGF) for angiogenesis (6, 18, 34). Hpse lacking catalytic enzyme activity has been shown to increase the expression of certain growth factors (35) and to facilitate cell binding to HS in the ECM and to endothelial cells in vitro (32). "
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    ABSTRACT: Heparanase (Hpse) is the only known mammalian endo-β-d-glucuronidase that degrades the glycosaminoglycan heparan sulfate (HS), found attached to the core proteins of heparan sulfate proteoglycans (HSPGs). Hpse plays a homeostatic role in regulating the turnover of cell-associated HS and also degrades extracellular HS in basement membranes (BMs) and the extracellular matrix (ECM), where HSPGs function as a barrier to cell migration. Secreted Hpse is harnessed by leukocytes to facilitate their migration from the blood to sites of inflammation. In the non-obese diabetic (NOD) model of autoimmune Type 1 diabetes (T1D), Hpse is also used by insulitis leukocytes to solubilize the islet BM to enable intra-islet entry of leukocytes and to degrade intracellular HS, an essential component for the survival of insulin-producing islet beta cells. Treatment of pre-diabetic adult NOD mice with the Hpse inhibitor PI-88 significantly reduced the incidence of T1D by ~50% and preserved islet HS. Hpse therefore acts as a novel immune effector mechanism in T1D. Our studies have identified T1D as a Hpse-dependent disease and Hpse inhibitors as novel therapeutics for preventing T1D progression and possibly the development of T1D vascular complications.
    Frontiers in Immunology 12/2013; 4:471. DOI:10.3389/fimmu.2013.00471
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