Mouse model of hepatocellular hyperplastic nodule formation characterization of mRNA expression

Abstract In previous studies a mouse model of hepatocellular tumorigenesis was developed. In this model of chronic griseofulvin feeding, preneoplastic foci developed over 5 months and numerous hyperplastic nodules with a few hepatocellular carcinomas developed after 10 months. In a subsequent study where 5- and 16-month livers were tested, the immediate early gene c-fos mRNA and transcription factor AP-1 were activated as well as was NFκB at both time intervals. However, the PPARα and RXRα genes were down-regulated. The evidence indicated that immediate early genes were involved in the promotion of tumor formation and that the direct hyperplasia pathway of regeneration was suppressed. To further characterize the involvement of the immediate early gene expression as well as other genes involved in the preneoplastic process we measured mRNA for c-jun, c-myc, hepatocyte growth factor activator (HGF-A), TGFβRII, γ-glutamyl transpeptidase (GGT), cytokeratin (CK8), ubiquitin (UB) and cellular transglutaminase (TG). The data indicated that c-jun an immediate early gene and c-myc, a delayed early gene were up-regulated at 5 and 16 months of feeding, both when preneoplastic foci appeared and when hyperplastic nodules developed. However, HGF-A was down-regulated at both time intervals. TGFβRII was up-regulated, as was GGT, CK8, TG and UB. GGT up-regulation was the only progression seen in gene expression at 16 months. It is concluded that a complex of cell proliferation and cell maintenance genes are involved in tumorigenesis in the mouse model of tumor promotion.