Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer.
生长激素诱导的信号转导子和转录激活子 5 信号引起巨人症、炎症和过早死亡,但保护小鼠免受侵袭性肝癌。

摘要

UNLABELLED: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.
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.

译文

未标记: 持续高水平的生长激素 (GH) 会导致肝癌。GH 激活多种信号转导途径,其中有 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 STAT5 的过度激活和缺失都与肝细胞癌 (HCC) 的发展有关; 然而, 由于高 GH 水平,STAT5 在肝癌发展中的作用仍然是个谜。因此,我们将由过度激活的 GH 信号 (GH (tg)) 引起的巨人症和炎症性肝癌的小鼠模型与肝脏缺失 STAT5 (Δ hep) 的小鼠杂交。与 GH (tg) 小鼠不同,GH (tg) STAT5 (Δ hep) 动物没有显示巨人症。此外,与慢性炎症相关的过早死亡,以及在 GH (tg) 小鼠中观察到的肝细胞病理改变,在 GH (tg) 缺乏 stat5 的动物中没有观察到。引人注目的是,肝脏 STAT5 蛋白的丢失导致 GH (tg) 小鼠中肝癌的发展增强。尽管慢性炎症减少,GH (tg) STAT5 (Δ hep) 小鼠显示比 GH (tg) 动物更早和更先进的肝癌。这可能归因于增加的外周脂肪分解、肝脏脂质合成、伴随着促进肿瘤的 c-6月的异常激活的保肝介质的丢失和 STAT3 信号级联的结合, 和 DNA 损伤的积累,继发于细胞周期控制的丧失。因此,在 STAT5 (Δ hep) 小鼠中从未观察到肝癌。
结论: 作为其保肝功能的结果,STAT5 蛋白在过度激活的 GH 信号设置中预防进行性脂肪肝和侵袭性肝癌的形成。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着关键作用。

Gigantism

内分泌 生长激素紊乱 疾病
概述  :  

巨人症是一种严重的疾病,主要由腺瘤(垂体的一种肿瘤)引起的。巨大症发生在儿童时期生长激素过多的患者中。垂体肿瘤细胞分泌过多的生长激素(GH),导致体内许多变化。巨人症通常出现在儿童期或成年期。如果在骨生长板融合后发展出分泌生长激素的垂体瘤,则表现为肢端肥大症。临床表现一般临床表现:巨人症相关的主要症状是身材高大,比同龄人高,肌肉和器官也可能会肿大。其他症状包括:青春期延迟;巨人症的症状与肢端肥大症患者有相似的身体变化,包括:手脚异常增大;远端手指和脚趾加宽,称为“桨状”脚趾;面部特征的变化可

Gigantism   英/dʒaɪˈɡæntɪzəm; ˈdʒaɪɡæntɪzəm/   美/dʒaɪˈɡæntɪzəm,ˈdʒaɪɡæntɪzəm/

释    义   n. 巨大;[内科] 巨人症;巨大畸形

例    句   Her gigantism is due to a tumor in her pituitary gland. 她的巨人症是由脑垂体肿瘤引起的。

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