Mouse model of hepatocellular hyperplastic nodule formation characterization of mRNA expression

In previous studies a mouse model of hepatocellular tumorigenesis was devel oped. In this model of chronic griseofulvin feeding, preneoplastic foci dev eloped over 5 months and numerous hyperplastic nodules with a few hepatocel lular 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 tr anscription factor AP-1 were activated as well as was NF kappa B at both ti me intervals. However. the PPAR alpha and RXR alpha genes were down-regulat ed. The evidence indicated that immediate early genes were involved in the promotion of tumor formation and that the direct hyperplasia pathway of reg eneration was suppressed. To further characterize the involvement of the im mediate early gene expression as well as other genes involved in the preneo plastic process we measured mRNA for c-jun, c-myc, hepatocyte growth factor activator (HGF-A), TGF beta RII, gamma-glutamyl transpeptidase (GGT), cyto keratin (CK8), ubiquitin (UB) and cellular transglutaminase (TG). The data indicated that c-jun an immediate early gene and c-myc, a delayed early gen e were up-regulated at 5 and 16 months of feeding, both when preneoplastic foci appeared and when hyperplastic nodules developed. However, HGF-A was d own-regulated at both time intervals. TGF beta RII was up-regulated, as was GGT, CK8, TG and UB. GGT up-regulation was the only progression seen in ge ne expression at 16 months. It is concluded that a complex of cell prolifer ation and cell maintenance genes are involved in tumorigenesis in the mouse model of tumor promotion. (C) 1999 Elsevier Science Ireland Ltd. All right s reserved.