title: Down-regulation of osteopontin inhibits metastasis of hepatocellular carcinoma cells via a mechanism involving MMP-2 and uPA.
abstract: Osteopontin (OPN) has an important role in hepatocellular carcinoma (HCC) progression and metastasis. This study was to investigate the therapeutic potential of inhibition of OPN expression. A 2'-O-methoxyethylribose-modified phosphorothioate antisense oligonucleotides (ASO) was used to knock-down OPN expression in the human metastatic HCC cell line HCCLM6 and in nude mice orthotopically implanted with HCCLM6 showing highly spontaneous lung metastasis. Furthermore, we assessed the metastatic potential of HCCLM6 cells in vitro and in vivo after ASO treatment. Treatment of HCCLM6 cells with OPN ASO inhibited OPN mRNA expression in a dose- and time-dependent manner, whereas the control oligonucleotides had no effect. OPN ASO significantly suppressed migration and invasion of HCCLM6 cells in vitro. Specific suppression of OPN also inhibited matrix metalloproteinase 2 (MMP-2) and urokinase-type plasminogen activator (uPA) expression in HCCLM6 cells. In mice bearing orthotopical xenografts with HCCLM6, OPN inhibition following therapeutic treatment with OPN ASO significantly decreased lung metastases although tumor weight did not appear to be reduced. These findings suggest that OPN-targeted therapy may be a promising strategy for the treatment of HCC metastases.
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
authors.forename: Rong-Xin
authors.initials: RX
authors.lastname: Chen
authors.forename: Yun-Hong
authors.initials: YH
authors.lastname: Xia
authors.forename: Tong-Chun
authors.initials: TC
authors.lastname: Xue
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Sheng-Long
authors.initials: SL
authors.lastname: Ye
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D053495:Osteopontin / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020319:Oligodeoxyribonucleotides, Antisense; D053495:Osteopontin; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2