Mutant Hras(G12V)  and Kras(G12D)  have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice.
BACKGROUND
Mouse hepatocarcinogenesis is associated with mutations in Hras, but infrequently in Kras. The effect on carcinogenesis of developmental age at the time of ras mutation remains unknown.


OBJECTIVE
We sought to compare quantitatively the effects of expressing mutant H- or Kras genes in fetal vs. adult mouse liver.


METHODS
We established an inducible system of gene expression in mouse liver to define disease pathogenesis associated with activation of oncogene expression.


RESULTS
Diffuse expression of either oncogene in fetal or adult hepatocytes caused hepatomegaly. For mutant Hras(G12V), this phenotype was almost fully reversible and accompanied by apoptosis, indicating that maintenance of hepatomegaly requires continuous Hras(G12V) expression. We also examined the effect of ras expression on growth of transplanted hepatocytes in an in vivo system that allows us to quantify hepatocyte growth effects in both permissive and restrictive hepatic growth environments. Mutant Kras(G12D) had no effect on hepatocyte growth in this system. In contrast, Hras(G12V) induced increased hepatocyte focus growth in quiescent liver, the hallmark of a cell autonomous growth stimulus. Hras(G12V) also increased the fraction of donor hepatocyte foci that displayed extreme growth, a characteristic of preneoplastic lesions.


CONCLUSIONS
The primary effect of diffuse, whole-liver expression of either mutant ras gene in fetal or adult mouse liver is diffuse and progressive hepatic growth. Hras(G12V) mutation influences hepatocarcinogenesis by conferring cell autonomous growth potential upon foci of expressing cells and by increasing the risk of neoplastic progression. Kras(G12D) does not share these latter carcinogenic effects in mouse liver.
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Marxa L
ML
Figueiredo
Timothy J
TJ
Stein
Adam
A
Jochem
Eric P
EP
Sandgren
D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D005333:Fetus / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism* / Q000502:physiology*; D008113:Liver Neoplasms / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000235:genetics
D017931:DNA Primers; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)