374 Gut and Liver, Vol. 5, No. 3, September 2011 broad spectrum of biological activities, HGF is most likely the physiological hepatotrophic factor that triggers or modulates liver regeneration. HGF induces HOC proliferation in a 2-AAF/ PHx rat model,50 and PGs induce HGF expression in skin fibro- blasts. In contrast, the inhibition of PG synthesis by dexametha- sone reduces HGF production in these cells.51 In the present study, c-Met and COX-2 protein levels increased during liver regeneration in the rat 2-AAF/PHx model, and COX-2 expres- sion decreased gradually following NS398 treatment in a time- dependent manner, suggesting that the effects of NS398 on HOC proliferation are mediated by a COX-2-dependent signal- ing pathway (data not shown). Our findings are consistent with those of a previous report, although a reduction in the number of oval cells is associated with a reduced incidence of liver cancer in mice.22 In the context of human chronic liver disease, these results are of considerable relevance, as liver regeneration is paralleled by changes in the number of hepatic progenitor cells, which can differentiate into hepatocytes and bile ductular cells. COX-2 expression in HOCs was upregulated following ex- posure to an HGF-containing medium after NS398 treatment. These results suggest that HGF has a proliferative effect on HOCs, and that COX-2 mediates the effects of HGF on HOC proliferation due to binding of the growth factor to the c-Met receptor on the HOC surface. Thus, COX-2 may be used with ECM and HGF to investigate the regulation of HOC proliferation during liver regeneration. There are some limitations to this study. First, the identifica- tion of the PGE2 receptors was preliminary; additional function- al assays are needed. Second, a clear organized analysis of the signal transduction mechanisms involved in HOC proliferation, including total and phosphorylated ERK and AKT, is required. In conclusion, we showed that COX-2 is expressed in acti- vated HOCs, which proliferate through COX-2, extracellular FN, and AKT signaling, during liver regeneration after acute liver injury. HGF also stimulated HOC proliferation by increasing COX-2 expression. Therefore, COX-2 plays an important role in HOC proliferation after liver injury. CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. ACKNOWLEDGEMENTS This study was supported by the SK Chemical Research Fund of The Korean Society of Gastroenterology. We are grateful to Bryon E. Petersen (University of Florida) for donating the DPPIV knockout rats. REFERENCES 1. Michalopoulos GK, DeFrances MC. Liver regeneration. 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