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.
Highlights
Liver cancer is the second most common cause of cancer-related death, and its incidence and mortality are prominent in East Asia, including Korea, Japan, and China [1]
In the in vitro study, OPN suppression led to lower mRNA and protein levels of epidermal growth factor receptor (EGFR) associated with the downregulation of c-Jun in Hep3B and Huh7 human hepatocellular carcinoma (HCC) cells lines, which resulted in increased apoptotic cell death in both cell lines
OPN has been found to play an important role in oncogenic processes contributing to HCC and liver cirrhosis [22, 23]
Summary
Liver cancer is the second most common cause of cancer-related death, and its incidence and mortality are prominent in East Asia, including Korea, Japan, and China [1]. Many studies have determined that various etiologies, including chronic hepatitis B or C viral infection and cirrhosis are important risk factors for HCC [2, 3]. Each factor or combination of these factors can give rise to an inflammatory response and DNA damage, which progress through chronic hepatitis, cirrhosis, and eventually HCC [4,5,6]. Nagoshi established that HCC-associated liver disease were strongly associated with the expression of OPN in various cells, including hepatocytes, Kupffer cells, and stellate cells [7]. OPN is a secreted glycophosphoprotein that acts a ligand for its receptors, including integrins and CD44 variants, and the interactions between OPN and its receptors promote a variety of signaling pathways that eventually result in tumor progression [8]. It is reasonable to conclude that OPN is a candidate biomarker and target for HCC therapy
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