title: PI-88 inhibits postoperative recurrence of hepatocellular carcinoma via disrupting the surge of heparanase after liver resection.
abstract: 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.
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China.
authors.forename: Bo-Yi
authors.initials: BY
authors.lastname: Liao
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Liu
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China.
authors.forename: Zao-Zhuo
authors.initials: ZZ
authors.lastname: Shen
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China. fan.jia@zs-hospital.sh.cn.|Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China. fan.jia@zs-hospital.sh.cn.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, People's Republic of China. zhou.jian@zs-hospital.sh.cn.|Institute of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China. zhou.jian@zs-hospital.sh.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology / Q000601:surgery*; D002465:Cell Movement / Q000187:drug effects; D005966:Glucuronidase / Q000097:blood / Q000502:physiology*; D006498:Hepatectomy; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology / Q000601:surgery*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009844:Oligosaccharides / Q000494:pharmacology*; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D009844:Oligosaccharides; D000099175:Heparanase; C120158:phosphomannopentaose sulfate
keywords: Adjuvant therapy; Heparanase; Hepatocellular carcinoma; PI-88; Recurrence