Get access

Minimal cooperation between mutant Hras and c-myc or TGFα in the regulation of mouse hepatocyte growth or transformation in vivo

Authors

  • 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.
    Search for more papers by this author
  • Margaret Bowden,

    1. Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
    Search for more papers by this author
  • Eric P. Sandgren

    Corresponding author
    • Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
    Search for more papers by this author

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: Liver carcinogenesis is associated with multiple genetic changes in affected cells, including alterations in the Hras signalling pathway. Aim: To define the biological contributions of Hras to mouse hepatocarcinogenesis, we quantified in vivo interactions between mutant Hras and other genetic alterations frequently associated with liver cancer, including overexpression of the transcription factor c-myc and the epidermal growth factor receptor ligand transforming growth factor alpha (TGFα). Methods: To accomplish this aim, we initiated expression of an activated Hras in hepatocytes of adult mice with or without simultaneous overexpression of either c-myc or TGFα. Potential interactions also were assessed through the use of the comparative hepatocyte growth assay, a hepatocyte transplantation assay that measures effects of altered gene expression on hepatocyte growth in vivo. Results: Hras expression caused diffuse liver enlargement (hepatomegaly), and this phenotype was not changed by coexpression of c-myc or TGFα. Using the transplant system, we found that expression of mutant Hras alone was sufficient to induce hepatocyte focus growth in a quiescent liver. Paradoxically, adding expression of TGFα or c-myc reversed this Hras effect. Finally, the frequencies of transplant foci with the preneoplastic feature of extreme growth potential and of liver neoplasms were increased for Hras and both combinations when compared with control hepatocytes, but did not differ among oncogene-expressing groups. Conclusions: Hras-associated hepatocyte growth deregulation is not complemented by activation of c-myc or TGFα growth signalling pathways in mouse liver. This finding emphasizes the tissue-specific character of molecular growth regulation.

Get access to the full text of this article

Ancillary