Regulation of ser‐45 mutated beta‐catenin in transgenic mouse livers

Abstract

Wnt/β‐catenin activation is frequently observed in hepatocellular carcinomas (HCC) due to multiple mechanisms. A common event is mutation at serine‐45 in β‐catenin rendering a stable protein. S45‐mutated β‐catenin was utilized to generate liver‐specific transgenic mice (Hep‐S45D‐Tg). Two independent lines were characterized and had a similar phenotype. Increased liver weight to body weight ratio from 10‐20% was observed in Hep‐S45D‐Tg (TG) relative to FVB wild‐type (WT). Increased levels of β‐catenin in the nucleus were observed at 1 month, which coincided with increased cyclin‐D1 and significantly higher Ki‐67‐positive hepatocytes. Interestingly, elevated β‐catenin was observed only at the hepatocyte membrane at 2 and 6 months with no change in proliferation but with an increase in average hepatocyte size. Decreased apoptosis was evident at 6 months only. No spontaneous tumors were observed in TG mice up to 12 months. DEN‐induced hepatocarcinogenesis was investigated in WT and TG mice. Females were protected up to 9 months. Male TG mice showed hepatic adenomas (HA) and HCC at 9 months, whereas WT mice showed HA only. Thus, TG mice demonstrated nuclear β‐catenin and activation that led to increased liver size at 1 month that was later regulated by sequestration of ‐catenin at the hepatocyte membrane. Also, TG mice showed higher incidence of HCC after DEN treatment.