Hosui Atsushi, Kimura Akiko, Yamaji Daisuke, Zhu Bing-mei, Na Risu, Hennighausen Lothar
Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Exp Med. 2009 Apr 13;206(4):819-31. doi: 10.1084/jem.20080003. Epub 2009 Mar 30.
The molecular mechanisms underlying the development of hepatocellular carcinoma are not fully understood. Liver-specific signal transducer and activator of transcription (STAT) 5A/B-null mice (STAT5-LKO) were treated with carbon tetrachloride (CCl(4)), and histological analyses revealed liver fibrosis and tumors. Transforming growth factor (TGF)-beta levels and STAT3 activity were elevated in liver tissue from STAT5-LKO mice upon CCl(4) treatment. To define the molecular link between STAT5 silencing and TGF-beta up-regulation, as well as STAT3 activation, we examined STAT5-null mouse embryonic fibroblasts and primary hepatocytes. These cells displayed elevated TGF-beta protein levels, whereas messenger RNA levels remained almost unchanged. Protease inhibitor studies revealed that STAT5 deficiency enhanced the stability of mature TGF-beta. Immunoprecipitation and immunohistochemistry analyses demonstrated that STAT5, through its N-terminal sequences, could bind to TGF-beta and that retroviral-mediated overexpression of STAT5 decreased TGF-beta levels. To confirm the in vivo significance of the N-terminal domain of STAT5, we treated mice that expressed STAT5 lacking the N terminus (STAT5-DeltaN) with CCl(4). STAT5-DeltaN mice developed CCl(4)-induced liver fibrosis but no tumors. In conclusion, loss of STAT5 results in elevated TGF-beta levels and enhanced growth hormone-induced STAT3 activity. We propose that a deregulated STAT5-TGF-beta-STAT3 network contributes to the development of chronic liver disease.
肝细胞癌发生发展的分子机制尚未完全明确。用四氯化碳（CCl₄）处理肝脏特异性信号转导及转录激活因子（STAT）5A/B基因敲除小鼠（STAT5-LKO），组织学分析显示出现肝纤维化和肿瘤。CCl₄处理后，STAT5-LKO小鼠肝脏组织中转化生长因子（TGF）-β水平及STAT3活性升高。为明确STAT5沉默与TGF-β上调以及STAT3激活之间的分子联系，我们检测了STAT5基因敲除的小鼠胚胎成纤维细胞和原代肝细胞。这些细胞中TGF-β蛋白水平升高，而信使核糖核酸水平几乎未变。蛋白酶抑制剂研究表明，STAT5缺乏增强了成熟TGF-β的稳定性。免疫沉淀和免疫组化分析显示，STAT5可通过其N端序列与TGF-β结合，逆转录病毒介导的STAT5过表达可降低TGF-β水平。为证实STAT5 N端结构域在体内的重要性，我们用CCl₄处理表达缺乏N端的STAT5（STAT5-ΔN）的小鼠。STAT5-ΔN小鼠出现CCl₄诱导的肝纤维化，但未发生肿瘤。总之，STAT5缺失导致TGF-β水平升高及生长激素诱导的STAT3活性增强。我们认为，失调的STAT5-TGF-β-STAT3网络促成了慢性肝病的发生发展。
