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


CONCLUSIONS
As a result of their hepatoprotective functions, STAT5 proteins prevent progressive fatty liver disease and the formation of aggressive HCC in the setting of hyperactivated GH signaling. At the same time, they play a key role in controlling systemic inflammation and regulating organ and body size.
Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
Katrin
K
Friedbichler
Madeleine
M
Themanns
Kristina M
KM
Mueller
Michaela
M
Schlederer
Jan-Wilhelm
JW
Kornfeld
Luigi M
LM
Terracciano
Andrey V
AV
Kozlov
Susanne
S
Haindl
Lukas
L
Kenner
Thomas
T
Kolbe
Mathias
M
Mueller
Kenneth J
KJ
Snibson
Markus H
MH
Heim
Richard
R
Moriggl
D000818:Animals; D049628:Body Size / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D005877:Gigantism / Q000503:physiopathology*; D013006:Growth Hormone / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000503:physiopathology*; D050356:Lipid Metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D061213:Mortality, Premature; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology*
D016755:Proto-Oncogene Proteins c-jun; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D013006:Growth Hormone