Research ArticleRole of Myc in hepatocellular proliferation and hepatocarcinogenesis

Background & AimsMyc is involved in cell growth, proliferation, apoptosis, energy metabolism, and differentiation. Whether it is essential for hepatocellular proliferation and carcinogenesis is unclear due to a lack of an efficient hepatocyte-specific Myc disruption model. This study used a novel genetic model to investigate the involvement of Myc in hepatocellular proliferation and hepatocarcinogenesis in mice.MethodsTemporal hepatocyte-specific Myc disruption was achieved by use of the tamoxifen-inducible Cre-ERT2 recombinase system under control of the serum albumin promoter. Hepatocyte proliferation was assessed by administering peroxisome proliferator-activated receptor α (PPARα) agonist Wy-14,643. A diethylnitrosamine-induced liver cancer model was used to evaluate the role of Myc in hepatocarcinogenesis.ResultsTamoxifen administration induced recombination of Myc specifically in hepatocytes of Mycfl/fl,ERT2-Cre mice. When treated with a known hepatocellular proliferative stimulus Wy-14,643, Mycfl/fl,ERT2-Cre mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to Mycfl/fl mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Mycfl/fl mouse livers, but not in Wy-14,643-treated Mycfl/fl,ERT2-Cre livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Mycfl/fl,ERT2-Cre and Mycfl/fl mice, consistent with no differences in the expression of several PPARα target genes involved in fatty acid β-oxidation. Moreover, when subjected to the diethylnitrosamine liver cancer bioassay, Mycfl/fl,ERT2-Cre mice exhibited a markedly lower incidence of tumor formation compared with Mycfl/fl mice.ConclusionsMyc plays an essential role in hepatocellular proliferation and liver tumorigenesis.