Reassessing HPSE in Ovarian Cancer: Beneficial After All?

Abstract Background Heparanase (HPSE) uniquely cleaves heparan sulfate, the main component of the outer layer of endothelial cell plasma membranes, promoting tumour invasion and dissemination. However, it can also enhance tumour immune surveillance and clearance. HPSE’s versatility extends to pro-thrombotic properties, such as the promotion of tissue factor release. Interestingly, elevated HPSE levels have been found in ovarian cancer (OC), which has a notably high incidence of venous thrombosis. Previously, single-nucleotide polymorphisms (SNPs) of HPSE were shown to modulate mRNA and protein levels, possibly predicting disease outcomes. Methods and Results Given the potential role of HPSE in OC, the implications of three SNPs - rs11099592, rs4364254 and rs4693608 – were investigated on OC patients. In the discovery cohort, rs11099592 TT genotype and rs4364254 C allele carriers showed lower survival time than their counterparts (log-rank test, p  = 0.025 and p  = 0.001, respectively). Validation cohort analysis confirmed the worse prognosis associated with the rs11099592 T allele and rs4364254 C allele in non-serous (log-rank test, p  = 0.016) and platinum-resistant (log-rank test, p  = 0.044) OC patients, respectively. The rs4364254 C allele was associated with reduced HPSE expression in peripheral blood components (PBCs; χ 2 , p  = 0.005), suggesting a protective role for HPSE in OC patients. Conclusions HPSE rs11099592 and rs4364254 showed prognostic value, with T and C allele carriers, respectively, displaying worse clinical outcomes. These results indicate that HPSE could enable a tumour microenvironment shift towards a less aggressive cancer behaviour, facilitating leukocyte migration and anti-tumour responses. Further research should explore the dual mechanisms of this protein to improve OC management.