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Type of publication: Journal Article
Type of document: Full Paper

Year: 2012

Authors: Friedbichler, K; Themanns, M; Mueller, KM; Schlederer, M; Kornfeld, JW; Terracciano, LM; Kozlov, AV; Haindl, S; Kenner, L; Kolbe, T; Mueller, M; Snibson, KJ; Heim, MH; Moriggl, R

Title: Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer.

Source: Hepatology. 2012; 55(3):941-952



Authors Vetmeduni Vienna:

Kenner Lukas
Kolbe Thomas
Moriggl Richard
Müller Kristina
Müller Mathias

Vetmed Research Units
Institut für In-vivo und In-vitro-Modelle
Institute of Animal Breeding and Genetics


Abstract:
Persistently high levels of growth hormone (GH) can cause liver cancer. GH activates multiple signal-transduction pathways, among them janus kinase (JAK) 2-signal transducer and activator of transcription (STAT) 5 (signal transducer and activator of transcription 5). Both hyperactivation and deletion of STAT5 in hepatocytes have been implicated in the development of hepatocellular carcinoma (HCC); nevertheless, the role of STAT5 in the development of HCC as a result of high GH levels remains enigmatic. Thus, we crossed a mouse model of gigantism and inflammatory liver cancer caused by hyperactivated GH signaling (GH(tg) ) to mice with hepatic deletion of STAT5 (STAT5(Δhep) ). Unlike GH(tg) mice, GH(tg) STAT5(Δhep) animals did not display gigantism. Moreover, the premature mortality, which was associated with chronic inflammation, as well as the pathologic alterations of hepatocytes observed in GH(tg) mice, were not observed in GH(tg) animals lacking STAT5. Strikingly, loss of hepatic STAT5 proteins led to enhanced HCC development in GH(tg) mice. Despite reduced chronic inflammation, GH(tg) STAT5(Δhep) mice displayed earlier and more advanced HCC than GH(tg) animals. This may be attributed to the combination of increased peripheral lipolysis, hepatic lipid synthesis, loss of hepatoprotective mediators accompanied by aberrant activation of tumor-promoting c-JUN and STAT3 signaling cascades, and accumulation of DNA damage secondary to loss of cell-cycle control. Thus, HCC was never observed in STAT5(Δhep) mice.

Keywords Pubmed: Animals
Body Size/physiology
Carcinoma, Hepatocellular/metabolism
Carcinoma, Hepatocellular/physiopathology
Carcinoma, Hepatocellular/prevention & control*
Disease Models, Animal
Fatty Liver/metabolism
Fatty Liver/physiopathology
Fatty Liver/prevention & control
Gigantism/physiopathology*
Growth Hormone/physiology*
Hepatocytes/metabolism
Hepatocytes/pathology
Inflammation/physiopathology*
Lipid Metabolism/physiology
Liver/metabolism
Liver/pathology
Liver Neoplasms/metabolism
Liver Neoplasms/physiopathology
Liver Neoplasms/prevention & control*
Mice
Mice, Transgenic
Mortality, Premature*
Proto-Oncogene Proteins c-jun/metabolism
STAT3 Transcription Factor/metabolism
STAT5 Transcription Factor/deficiency
STAT5 Transcription Factor/genetics
STAT5 Transcription Factor/physiology*
Sheep
Signal Transduction/physiology*


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