PI-88 inhibits postoperative recurrence of hepatocellular carcinoma via disrupting the surge of heparanase after liver resection

摘要

Phosphomannopentaose sulfate (PI-88), an effective inhibitor of heparanase (HPSE), exhibited anti-recurrence and anti-metastasis activity in preliminary clinical trials of hepatocellular carcinoma (HCC); however, the underlying mechanisms remain uncertain. Our aim was to reveal the mechanism by which PI-88 inhibits recurrence and intrahepatic metastasis. A tissue microarray containing samples from 352 HCC patients was used to determine HPSE expression. We performed enzyme-linked immunosorbent assay (ELISA) to detect plasma levels of HPSE in 40 HCC patients. We also used quantitative polymerase chain reaction, western blot analysis, and immunohistochemical staining to assess HPSE expression of HCC cell lines and tissues. The in vitro effects of PI-88 were examined by cell proliferation and migration assays. In vivo PI-88 activity was assessed using murine orthotopic HCC models. Intratumoral HPSE was an independent prognostic marker for postsurgical overall survival (P = 0.001) and time to recurrence (P < 0.001) of HCC patients with hepatectomy. Elevated levels of HPSE were detected both in postsurgical plasma of HCC patients and an orthotopic mouse model after hepatectomy. PI-88 inhibited tumor recurrence and metastasis after liver resection in the mouse model. In vitro expression of HPSE was up-regulated by overexpression of early growth response 1 (EGR1), which is induced after hepatectomy. Up-regulation of HPSE enhanced the sensitivity of HCC cells to PI-88 and the inhibitive effect of PI-88 on cell proliferation and migration. Our data show that PI-88 effectively inhibits postoperative recurrence and intrahepatic metastasis of HCC, providing an experimental basis for the clinical application of PI-88 in HCC patients who have undergone hepatectomy.