Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer
Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer
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DOI：
10.1002/hep.24765
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发表时间：
2012-03-01
期刊：
影响因子：
13.5
通讯作者：
Moriggl, Richard
中科院分区：
文献类型：
--
作者：
Friedbichler, Katrin;Themanns, Madeleine;Moriggl, Richard
持续高水平的生长激素（GH）可导致肝癌。GH激活多种信号转导途径，其中包括Janus激酶（JAK）2-信号转导子和转录激活子（STAT）5（信号转导子和转录激活子5）。肝细胞中STAT 5的过度激活和缺失都与肝细胞癌（HCC）的发生有关;然而，由于高GH水平，STAT 5在HCC发生中的作用仍然是个谜。因此，我们将由过度活化的GH信号传导（GHtg）引起的肥胖症和炎性肝癌的小鼠模型与肝脏缺失STAT 5（STAT 5？hep）。与GHtg小鼠不同，GHtgSTAT 5？hep动物没有表现出过敏。此外，与慢性炎症相关的过早死亡，以及在GHTG小鼠中观察到的肝细胞的病理学改变，在缺乏STAT 5的GHTG动物中未观察到。引人注目的是，肝脏STAT 5蛋白的丢失导致GHtg小鼠中HCC发展增强。尽管减少慢性炎症，GHtgSTAT 5？hep小鼠比GHtg动物显示出更早和更晚期的HCC。这可能归因于外周脂解增加、肝脂质合成、伴随肿瘤促进c-JUN和STAT 3信号级联的异常激活的肝保护介质的丧失以及继发于细胞周期控制丧失的DNA损伤累积的组合。因此，肝癌从来没有观察到STAT 5？hep老鼠结论：由于它们的肝脏保护功能，STAT 5蛋白在过度活化的GH信号传导的情况下预防进行性脂肪肝疾病和侵袭性HCC的形成。同时，它们在控制全身炎症和调节器官和身体大小方面发挥关键作用。（肝病学2012）
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 (STAT5?hep). Unlike GHtg mice, GHtgSTAT5?hep 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, GHtgSTAT5?hep 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 STAT5?hep 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)