Functional analysis of osteoactivin and its role in hepatocarcinogenesis

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Hepatocellular carcinoma (HCC) is closely associated with chronic liver disease, particularly cirrhosis. The aim of this study is to identify genes associated with early cirrhosis-associated hepatocarcinogenesis. First, we examined sequential changes in expression of growth factors, and hepatocyte proliferation and apoptosis during hepatocarcinogenesis in rats fed a choline-deficient, L-amino acid-defined (CDAA) diet. In this rat model, HCCs occur in conjunction with fatty liver, hepatocyte death and subsequent regeneration, fibrosis, and eventual cirrhosis. Expression of hepatocyte growth factor (HGF) was stimulated at about the same time as CDAA diet-induced liver injury within 1 week. HGF reached a maximum level of expression from 4 to 8 weeks. Although hepatocyte proliferation continued to be stimulated throughout the experimental period, the number of apoptotic hepatocytes was markedly reduced after peaking at 8 weeks. These findings suggest that a disruption of the normal balance between hepatocyte proliferation and apoptosis early in the CDAA diet promotes the survival of cells capable of malignant transformation. Therefore, we next examined genes differentially expressed in the livers of normal rats and rats fed the CDAA diet for 8 weeks, and isolated, osteoactivin (OA) cDNA. OA mRNA was strongly expressed in the livers of rats fed the CDAA diet for 1-3 months. Moderate expression was sustained for 18 months. OA overexpression increased the invasiveness and metastasis of rat hepatoma cells. In humans, while GA transcripts were detectable in cirrhotic nontumorous liver tissues surrounding HCCs, the majority of HCC tissue samples exhibited higher levels of OA expression than the surrounding normal tissue. These results indicate that OA is a novel factor involved in the progression of HCC via stimulation of tumor invasiveness and metastatic potential.