Background & aims: Myc 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.
Methods: Temporal hepatocyte-specific Myc disruption was achieved by use of the tamoxifen-inducible Cre-ER(T2) 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.
Results: Tamoxifen administration induced recombination of Myc specifically in hepatocytes of Myc(fl/fl,ERT2-Cre) mice. When treated with a known hepatocellular proliferative stimulus Wy-14,643, Myc(fl/fl,ERT2-Cre) mice showed a lower liver/body weight ratio and suppressed hepatocyte proliferation as compared to Myc(fl/fl) mice. Hepatic expression of cell cycle control genes, DNA repair genes, and Myc target gene miRNAs were upregulated in Wy-14,643-treated Myc(fl/fl) mouse livers, but not in Wy-14,643-treated Myc(fl/fl,ERT2-Cre) livers. However, no differences were observed in the lipid-lowering effect of Wy-14,643 between Myc(fl/fl,ERT2-Cre) and Myc(fl/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, Myc(fl/fl,ERT2-Cre) mice exhibited a markedly lower incidence of tumor formation compared with Myc(fl/fl) mice.
Conclusions: Myc plays an essential role in hepatocellular proliferation and liver tumorigenesis.
Keywords: Acox1; BrdU; CDK; Cell cycle control; Cell proliferation; Chek1; Cre-ER(T2); Cyp4a10 and Cyp4a14; DEN; Mcm; Myc; Myc(fl/fl); Myc(fl/fl)Mx-Cre; Myc(fl/fl,ERT2-Cre); PPARα; RAD51 homolog (S. cerevisiae); Rad51; SA; Tumorigenesis; acyl-CoA oxidase; bHLH; basic helix-loop-helix leucine zipper; bromodeoxyuridine; checkpoint kinase 1 homologue; cre recombinase, tamoxifen-inducible estrogen receptor ligand-binding domain fusion protein; cyclin-dependent kinase; cytochromes P450 4a10 and 4a14; diethynitrosamine; floxed Myc allele; inducible liver-specific Myc knockout mouse; minichromosome maintenance; peroxisome proliferator-activated receptor α; serum albumin promoter; α/β interferon-inducible Mx-promoter driving Cre recombinase.
Published by Elsevier B.V.