title: Suppression of osteopontin inhibits chemically induced hepatic carcinogenesis by induction of apoptosis in mice.
abstract: Previous clinical reports have found elevated osteopontin (OPN) levels in tumor tissues to be indicative of greater malignancy in human hepatocellular carcinoma (HCC). However, the role of OPN on carcinogenesis and its underlying mechanism remain unclear. In the present study, we investigated the oncogenic role of OPN in diethylnitrosamine (DEN)-induced hepatic carcinogenesis in mice. The overall incidence of hepatic tumors at 36 weeks was significantly lower in OPN knockout (KO) mice than in wild-type (WT) mice. Apoptosis was significantly enhanced in OPN KO mice, and was accompanied by the downregulation of epidermal growth factor receptor (EGFR). In the in vitro study, OPN suppression also led to lower mRNA and protein levels of EGFR associated with the downregulation of c-Jun in Hep3B and Huh7 human HCC cells lines, which resulted in increased apoptotic cell death in both cell lines. Moreover, a positive correlation was clearly identified between the expression of OPN and EGFR in human HCC tissues. These data demonstrate that the OPN deficiency reduced the incidence of chemically induced HCC by suppressing EGFR-mediated anti-apoptotic signaling. An important implication of our findings is that OPN positively contributes to hepatic carcinogenesis.
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Su-Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi 410-769, South Korea.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Du-Min
authors.initials: DM
authors.lastname: Go
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 305-764, South Korea.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Pathology, College of Medicine, Seoul National University, Seoul 110-799, Korea.
authors.forename: Ja-June
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004052:Diethylnitrosamine; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D053495:Osteopontin; D004052:Diethylnitrosamine; D066246:ErbB Receptors
keywords: EGFR; apoptosis; c-Jun; hepatocellular carcinoma; osteopontin