Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production
Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production
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DOI：
10.1038/sj.onc.1209281
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
--
作者：
Ogata, H;Chinen, T;Yoshimura, A
最近，有报道称人肝细胞癌（HCC）患者的DNA甲基化和细胞因子信号传导-3 （SOCS3）基因抑制子的表达降低。然而，SOCS3在体内HCC发展中的作用尚未明确。通过RT-PCR分析和Western blotting，我们证实SOCS3在HCC患者中的表达降低。然而，SOCS3的表达减少不仅发生在HCC中，也发生在非肿瘤区域，并且随着纤维化级别的增加，这种减少更强烈。此外，在非hcc区域，SOCS3水平与信号转导和转录-3激活因子（STAT3）激活以及转化生长因子(TGF)- β 1水平呈负相关。为了阐明SOCS3沉默/STAT3过度激活和肝纤维化的分子后果，我们研究了肝脏特异性SOCS3缺陷小鼠。我们证明肝脏中SOCS3的缺失导致STAT3的过度激活，并促进ConA和化学诱导的肝纤维化。tgf - β 1（一种纤维化介质）的表达通过SOCS3基因缺失而增强，但在体内和体外均被显性阴性STAT3或SOCS3的过表达所抑制。这些数据表明，tgf - β 1是STAT3的靶基因，可能是socs3缺陷小鼠纤维化增强的机制之一。因此，我们目前的研究提供了SOCS3和STAT3在HCC发展中的新作用：除了先前表征的致癌潜力外，STAT3通过上调tgf - β 1表达来增强肝纤维化，而SOCS3阻止了这一过程。
Recently, DNA methylation and reduced expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in human hepatocellular carcinoma (HCC) patients have been reported. However, the roles of SOCS3 in HCC development in vivo have not been clarified. Using RT-PCR analysis and Western blotting, we confirmed that SOCS3 expression was reduced in HCC patients. However, reduced expression of SOCS3 occurred not only in HCC but also in nontumor regions, and this reduction was stronger as the fibrosis grade increased. Furthermore, SOCS3 levels were inversely correlated with signal transducers and activators of transcription-3 (STAT3) activation as well as transforming growth factor (TGF)-beta 1 levels in the non-HCC region. To de. ne the molecular consequences of SOCS3 silencing/STAT3 hyperactivation and liver fibrosis, we examined liver-specific SOCS3-deficient mice. We demonstrated that SOCS3 deletion in the liver resulted in hyperactivation of STAT3 and promoted ConA- and chemical-induced liver fibrosis. The expression of TGF-beta 1, a mediator of fibrosis, was enhanced by SOCS3 gene deletion, but suppressed by the overexpression of a dominant-negative STAT3 or SOCS3 both in vivo and in vitro. These data suggest that TGF-beta 1 is a target gene of STAT3 and could be one of the mechanisms for enhanced fibrosis in SOCS3-deficient mice. Thus, our present study provides a novel role of SOCS3 and STAT3 in HCC development: in addition to the previously characterized oncogenic potentials, STAT3 enhances hepatic fibrosis through the upregulation of TGF-beta 1 expression, and SOCS3 prevents this process.