Suppression of osteopontin inhibits chemically induced hepatic carcinogenesis by induction of apoptosis in mice
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Su-Hyung Lee1, Jun-Won Park2, Sang-Ho Woo1, Du-Min Go1, Hyo-Jung Kwon3, Ja-June Jang4, Dae-Yong Kim1
1Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea
2Biomolecular Function Research Branch, National Cancer Center, Goyang, Gyeonggi 410-769, South Korea
3Department of Veterinary Pathology, College of Veterinary Medicine, Chungnam National University, Daejeon 305-764, South Korea
4Department of Pathology, College of Medicine, Seoul National University, Seoul 110-799, Korea
Dae-Yong Kim, email: [email protected]
Keywords: osteopontin, EGFR, c-Jun, apoptosis, hepatocellular carcinoma
Received: April 29, 2016 Accepted: November 01, 2016 Published: November 23, 2016
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.
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