Abstract
ObjectivesThe role of heparanase (HPSE) gene in cancers including hepatocellular carcinoma (HCC) is currently controversial. This study was aimed at investigating the impact of genetic alteration and expression change of HPSE on the progression and prognosis of HCC.MethodsThe HPSE gene was studied in three different aspects: (1) loss of heterozygosity (LOH) by a custom SNP microarray and DNA copy number by real-time PCR; (2) mRNA level by qRT-PCR; and (3) protein expression by immunohistochemistry. The clinical significances of allele loss and expression change of HPSE were analyzed.ResultsMicroarray analysis showed that the average LOH frequency for 10 SNPs located within HPSE gene was 31.6%, three of which were significantly correlated with tumor grade, serum HBV-DNA level, and AFP concentration. In agreement with SNP LOH data, DNA copy number loss of HPSE was observed in 38.74% (43/111) of HCC cases. HPSE mRNA level was notably reduced in 74.1% (83/112) of tumor tissues compared with non-tumor liver tissues, which was significantly associated with DNA copy number loss, increased tumor size, and post-operative metastasis. HPSE protein level was also remarkably reduced in 66.3% (53/80) of tumor tissues, which was correlated with tumor grade. Patients with lower expression level of HPSE mRNA or protein had a significantly lower survival rate than those with higher expression. Cox regression analysis suggested that HPSE protein was an independent predictor of overall survival in HCC patients.ConclusionsThe results in this study demonstrate that genetic alteration and reduction of HPSE expression are associated with tumor progression and poor prognosis of HCCs, suggesting that HPSE behaves like a tumor suppressor gene and is a potential prognostic marker for HCC patients.
Highlights
Heparanase (HPSE) is an endoglycosidase that cleaves side chains of heparan sulfate (HS), a linear polysaccharide found on the cell surface and extracellular matrix (ECM), which plays critical roles in cell-cell and cell-matrix interactions [1]
Our results suggest that HPSE is a tumor suppressor gene based on the fact that tumor suppressor gene usually has loss of heterozygosity (LOH) in carcinogenesis
Our results show that the allele loss and reduced HPSE expression are closely correlated with tumor progression and poor prognosis of hepatocellular carcinoma (HCC) patients
Summary
Heparanase (HPSE) is an endoglycosidase that cleaves side chains of heparan sulfate (HS), a linear polysaccharide found on the cell surface and extracellular matrix (ECM), which plays critical roles in cell-cell and cell-matrix interactions [1]. Many studies have shown that HPSE is up-regulated in a variety of primary human tumors, which is correlated with higher incidence of lymph node and distant metastasis, increased micro-vessel density and reduced post-operation survival of cancer patients [7,8]. These studies suggested that HPSE behaves like an oncogene or tumor promoter. Conflicting results were reported in hepatocellular carcinoma (HCC) [12] It remains unclear whether PHSE is a suppressor or promoter of human cancers, especially for HCC [12], which is possibly related to the extensive and complex functions of HPSE
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