Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine‐45 mutant β‐catenin

The Wnt/β‐catenin pathway is implicated in the pathogenesis of hepatocellular cancer (HCC). We developed a transgenic mouse (TG) in the FVB strain that overexpresses Ser45‐mutated‐β‐catenin in hepatocytes to study the effects on liver regeneration and cancer. In the two independent TG lines adult mice show elevated β‐catenin at hepatocyte membrane with no increase in the Wnt pathway targets cyclin‐D1 or glutamine synthetase. However, TG hepatocytes upon culture exhibit a 2‐fold increase in thymidine incorporation at day 5 (D5) when compared to hepatocytes from wildtype FVB mice (WT). When subjected to partial hepatectomy (PH), dramatic increases in the number of hepatocytes in S‐phase are evident in TG at 40 and WT at 72 hours. Coincident with the earlier onset of proliferation, we observed nuclear translocation of β‐catenin along with an increase in total and nuclear cyclin‐D1 protein at 40 hours in TG livers. To test if stimulation of β‐catenin induces regeneration, we used hydrodynamic delivery of Wnt‐1 naked DNA to control mice, which prompted an increase in Wnt‐1, β‐catenin, and known targets, glutamine synthetase (GS) and cyclin‐D1, along with a concomitant increase in cell proliferation. β‐Catenin‐overexpressing TG mice, when followed up to 12 months, showed no signs of spontaneous tumorigenesis. However, intraperitoneal delivery of diethylnitrosamine (DEN), a known carcinogen, induced HCC at 6 months in TG mice only. Tumors in TG livers showed up‐regulation of β‐catenin, cyclin‐D1, and unique genetic aberrations, whereas other canonical targets were unremarkable. Conclusion: β‐Catenin overexpression offers growth advantage during liver regeneration. Also, whereas no spontaneous HCC is evident, β‐catenin overexpression makes TG mice susceptible to DEN‐induced HCC. HEPATOLOGY 2010