Details

Autor(en) / Beteiligte

• Nejak-Bowen, Kari N
• Thompson, Michael D
• Singh, Sucha
• Bowen, William C
• Dar, Mohd Jamal
• Khillan, Jaspal
• Dai, Chunsun
• Monga, Satdarshan PS

Titel

Accelerated liver regeneration and hepatocarcinogenesis in mice overexpressing serine-45 mutant [beta]-catenin

Ist Teil von

• Hepatology (Baltimore, Md.), 2010-05, Vol.51 (5), p.1603

Ort / Verlag

Hoboken: Wiley Subscription Services, Inc

Erscheinungsjahr

2010

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• The Wnt/[beta]-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-[beta]-catenin in hepatocytes to study the effects on liver regeneration and cancer. In the two independent TG lines adult mice show elevated [beta]-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 [beta]-catenin along with an increase in total and nuclear cyclin-D1 protein at 40 hours in TG livers. To test if stimulation of [beta]-catenin induces regeneration, we used hydrodynamic delivery of Wnt-1 naked DNA to control mice, which prompted an increase in Wnt-1, [beta]-catenin, and known targets, glutamine synthetase (GS) and cyclin-D1, along with a concomitant increase in cell proliferation. [beta]-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 [beta]-catenin, cyclin-D1, and unique genetic aberrations, whereas other canonical targets were unremarkable. Conclusion: [beta]-Catenin overexpression offers growth advantage during liver regeneration. Also, whereas no spontaneous HCC is evident, [beta]-catenin overexpression makes TG mice susceptible to DEN-induced HCC. HEPATOLOGY 2010