Heparanase/Syndecan-1 Axis Regulates the Grade of Liver Cancer and Proliferative Ability of Hepatocellular Carcinoma Cells

Abstract

Background: Although heparanase/syndecan-1 axis is involved in malignant progression of many cancers, its significance in liver cancer is not well understood. In this study, we explored the value of heparanase/syndecan-1 axis expression in liver cancer and the intervention mechanisms that target this axis by inhibiting the proliferation of hepatocellular carcinoma cells. Materials and Methods: We conducted tissue microarray analysis that included 90 primary liver cancer and their corresponding adjacent samples to evaluate the expression of heparanase and syndecan-1 and their correlation with clinicopathologic characteristics. RNA interference and western blot assays were performed to analyze the effect of heparanase on syndecan-1 expression in human hepatocellular carcinoma cells MHCC97-H. Cell proliferative capability, Erk and Akt signaling molecules were respectively detected with CCK- 8, cell colony formation and western blot assays after the treatment of low molecular weight heparin (LMWH) and syndecan-1 monoclonal antibody. Results: Heparanase showed a high positive rates (75.56%) in liver cancer patients. The cellular positivity for membrane-located syndecan-1 was less in liver cancer (36.67%) compared with adjacent tissue (57.78%, P < 0.05). Heparanase expression was positively correlated with tumor grade, stages, and Ki- 67 expression (P < 0.05). In contradistinction, both cytoplasmic and membranal syndecan-1 expression exhibited negative correlations with tumor grade, stages, and Ki-67 expression (P < 0.05). Transfection with a heparanase small-interfering RNA resulted in a significant rise in membrane syndecan-1 expression but a marked decline in shed syndecan-1. LMWH and syndecan-1 monoclonal antibody notably inhibited cellular proliferation. Further studies revealed that LMWH and syndecan-1 monoclonal antibody significantly down-regulated Erk and Akt phosphorylation. Conclusions: Heparanase and syndecan-1 present a contrary correlation with the malignant capability of liver cancer, but work together to facilitate the proliferation of hepatocellular carcinoma cells that can be attenuated by LMWH and syndecan-1 monoclonal antibody by inhibiting Erk and Akt signals.