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

Katrin Friedbichler, Madeleine Themanns, Kristina M. Mueller, Michaela Schlederer, Jan Wilhelm Kornfeld, Luigi M. Terracciano, Andrey V. Kozlov, Susanne Haindl, Lukas Kenner, Thomas Kolbe, Mathias Mueller, Kenneth J. Snibson, Markus H. Heim, Richard Moriggl*

*Kontaktforfatter

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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 tgSTAT5 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 tgSTAT5 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. Conclusion: 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. (Hepatology 2012)

OriginalsprogEngelsk
TidsskriftHepatology (Baltimore, Md.)
Vol/bind55
Udgave nummer3
Sider (fra-til)941-952
ISSN0270-9139
DOI
StatusUdgivet - mar. 2012
Udgivet eksterntJa

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