Modification of heparanase gene expression in response to conditioning and LPS treatment: strong correlation to rs4693608 SNP

Abstract

Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of HSPGs, important structural and functional components of the ECM. Cleavage of HS leads to loss of the structural integrity of the ECM and release of HS-bound cytokines, chemokines, and bioactive angiogenic- and growth-promoting factors. Our previous study revealed a highly significant correlation of HPSE gene SNPs rs4693608 and rs4364254 and their combination with the risk of developing GVHD. We now demonstrate that HPSE is up-regulated in response to pretransplantation conditioning, followed by a gradual decrease thereafter. Expression of heparanase correlated with the rs4693608 HPSE SNP before and after conditioning. Moreover, a positive correlation was found between recipient and donor rs4693608 SNP discrepancy and the time of neutrophil and platelet recovery. Similarly, the discrepancy in rs4693608 HPSE SNP between recipients and donors was found to be a more significant factor for the risk of aGVHD than patient genotype. The rs4693608 SNP also affected HPSE gene expression in LPS-treated MNCs from PB and CB. Possessors of the AA genotype exhibited up-regulation of heparanase with a high ratio in the LPS-treated MNCs, whereas individuals with genotype GG showed down-regulation or no effect on HPSE gene expression. HPSE up-regulation was mediated by TLR4. The study emphasizes the importance of rs4693608 SNP for HPSE gene expression in activated MNCs, indicating a role in allogeneic stem cell transplantation, including postconditioning, engraftment, and GVHD.

Heparanase: From basic research to therapeutic applications in cancer and inflammation

“…Thus, it appears that in patients undergoing chemotherapy, NF-κB undergoes activation, leading to upregulation of heparanase. This is consistent with our finding that in the majority of multiple myeloma patients studied, the tumor cells which survived chemotherapy had elevated heparanase expression compared to baseline levels measured prior to therapy (Ostrovsky et al, 2014; Ramani et al, 2015) (Fig. 6C).…”

“…Briefly, we found that heparanase-high cells (i.e., myeloma, glioma, head & neck) were more resistant to killing by cytotoxic drugs than were heparanase-low cells (Ramani et al, 2016; Shteingauz et al, 2015). In addition, exposure to chemotherapeutic drugs dramatically increased heparanase synthesis and secretion in tumor cells that survive treatment (Ostrovsky et al, 2014; Ramani et al, 2016; Ramani et al, 2015). The secreted heparanase is likely performing an important pro-survival function by priming the tumor microenvironment to better support tumor growth.…”

“…Also, treatment of prostate cancer cells with the methylation inhibitor 5′-aza-2-deoxycytidine was found to upregulate heparanase expression (Ogishima et al, 2005). Importantly, heparanase is up-regulated (both at the mRNA and protein levels) in patients with various hematological malignancies following high dose chemotherapy (conditioning) prior to bone marrow transplantation (Ostrovsky et al, 2014; Ramani et al, 2015) (Fig. 6C).…”

Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype

“…Although these cells were marked for apoptosis and would eventually die, we found that they had upregulated, and were actively synthesizing, heparanase. We believe this is due to the tumor cell response to stress, stress being previously demonstrated to upregulate heparanase expression [37]. We found upregulated heparanase expression was linked to activation of NF-κB (Fig.…”

NK cell heparanase controls tumor invasion and immune surveillance

“…Besides tumor cells, a number of normal cell types, such as endothelial and immune cells including NK cells, express heparanase (17). Recently generated heparanase gene-targeted (Hpse-targeted) mice were used to investigate the role of heparanase in immune cell subtypes in response to different stimuli.…”