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Article first published online: 13 JAN 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 3, pages 941–952, March 2012
How to Cite
Friedbichler, K., Themanns, M., Mueller, K. M., Schlederer, M., Kornfeld, J.-W., Terracciano, L. M., Kozlov, A. V., Haindl, S., Kenner, L., Kolbe, T., Mueller, M., Snibson, K. J., Heim, M. H. and Moriggl, R. (2012), Growth-hormone–induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer. Hepatology, 55: 941–952. doi: 10.1002/hep.24765
Potential conflict of interest: Nothing to report.
This work and K.F., M.T., K.M., and J.W.K. were supported by grant SFB F28 from the Austrian Science Fund (FWF; to R.M. and M.M.) and the GEN-AU Program Projects “Austromouse” and “InflammoBiota” from the Austrian Federal Ministry for Science and Research (to M.M.). J.W.K. was also supported by a postdoctoral fellowship from the European Molecular Biology Organization.
- Issue published online: 23 FEB 2012
- Article first published online: 13 JAN 2012
- Accepted manuscript online: 26 OCT 2011 09:23AM EST
- Manuscript Accepted: 4 OCT 2011
- Manuscript Received: 12 MAY 2011
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 (GHtg) to mice with hepatic deletion of STAT5 (STAT5Δhep). Unlike GHtg mice, GHtgSTAT5Δhep 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 GHtg mice, were not observed in GHtg animals lacking STAT5. Strikingly, loss of hepatic STAT5 proteins led to enhanced HCC development in GHtg mice. Despite reduced chronic inflammation, GHtgSTAT5Δhep mice displayed earlier and more advanced HCC than GHtg 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 STAT5Δhep 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)