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

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 Dhep ). Unlike GH tg mice, GH tg STAT5 Dhep 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 Dhep 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 Dhep 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;55:941-952)

Hepatocellular alterations and dysregulation of oncogenic pathways in the liver of transgenic mice overexpressing growth hormone

“…Both NF-κB and STAT3 are known to play an important role in liver inflammation (He and Karin, 2011). Consistent with reported high hepatic expression of IL-6 in GH-transgenic mice (Friedbichler et al, 2012), elevated levels of activated STAT3 in this work are shown in both sexes in young adult and in old GH-transgenic mice liver. If the high STAT3 phosphorylation levels are a consequence of GH induced NF-κB expression or due to elevated levels of other growth factors and cytokines, as occurs in this animal model, needs to be elucidated.…”

“…That does not apply for males, which exhibit slightly higher STAT5 phosphorylation levels in normal than in transgenic mice. These results seem to contradict a recent publication, in which loss of STAT5 was proposed to controverse alterations induced by persistently high GH levels like increased hepatocyte size and turnover (Friedbichler et al, 2012). It is possible that tyrosine phosphorylation levels of this protein in whole tissue homogenates are not a direct reflection of the effective activity of STAT5 in GH-transgenic mice, as other factors are involved in its transcriptional activation.…”

“…In this study, NF-κB expression is increased in the liver of GHtransgenic mice compared to normal controls. As a recent study showed increased RelA mRNA and p65 positive inflammatory cells in GH-overexpressing mice (Friedbichler et al, 2012), the increase of NF-κB is most probably the result of the hepatic inflammation in this model. Already mentioned, NF-κB expands its range of modulation via crosstalk to different signaling cascades.…”

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

“…Firstly, we studied the morphology of the GH tg and wild type kidneys by performing H&E staining. GH tg mice were previously shown to exhibit polycystic kidneys 21 . We confirmed that the kidneys of GH tg mice exhibited multiple renal tubular dilatations when compared to the kidneys of wild-type mice ( Figure 6A).…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…Surprisingly, wild-type JAK2 decreases detoxifying glutathione S-transferases in epithelial cells, enhancing oxidative damage. In contrast, expression of anti-oxidative scavengers are under the control of STAT5, illustrating the interplay between JAK2 and STAT5 in balancing ROS action [117,118]. RAD51 members are conserved down to the E. coli RecA proteins and they are essential for DNA repair, which is downstream of cytokine- or TK-STAT signaling in mammalian cells [119,120].…”