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Mutant HrasG12V and KrasG12D have overlapping, but non-identical effects on hepatocyte growth and transformation frequency in transgenic mice

Authors

  • Marxa L. Figueiredo,

    1. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
    Current affiliation:
    1. University of Texas Medical Branch, 301 University Blvd, Department of Pharmacology & Toxicology, Galveston, TX, USA
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  • Timothy J. Stein,

    1. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
    Current affiliation:
    1. Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
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  • Adam Jochem,

    1. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
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  • Eric P. Sandgren

    Corresponding author
    • Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
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Correspondence

Dr Eric P. Sandgren, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA

Tel: 608-263-8870

Fax: 608-265-8435

e-mail: sandgren@svm.vetmed.wisc.edu; sandgren@rarc.wisc.edu

Abstract

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.

Aim

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 HrasG12V, this phenotype was almost fully reversible and accompanied by apoptosis, indicating that maintenance of hepatomegaly requires continuous HrasG12V 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 KrasG12D had no effect on hepatocyte growth in this system. In contrast, HrasG12V induced increased hepatocyte focus growth in quiescent liver, the hallmark of a cell autonomous growth stimulus. HrasG12V 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. HrasG12V mutation influences hepatocarcinogenesis by conferring cell autonomous growth potential upon foci of expressing cells and by increasing the risk of neoplastic progression. KrasG12D does not share these latter carcinogenic effects in mouse liver.

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