title: Minimal cooperation between mutant Hras and c-myc or TGFα in the regulation of mouse hepatocyte growth or transformation in vivo.
abstract: BACKGROUND
  Liver carcinogenesis is associated with multiple genetic changes in affected cells, including alterations in the Hras signalling pathway.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stein
authors.forename: Margaret
authors.initials: M
authors.lastname: Bowden
authors.forename: Eric P
authors.initials: EP
authors.lastname: Sandgren
mesh_terms: D018248:Adenoma, Liver Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D006529:Hepatomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016211:Transforming Growth Factor alpha; D018631:ras Proteins
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