Ogata H, Chinen T, Yoshida T, Kinjyo I, Takaesu G, Shiraishi H, Iida M, Kobayashi T, Yoshimura A
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Fukuoka, Japan.
Oncogene. 2006 Apr 20;25(17):2520-30. doi: 10.1038/sj.onc.1209281.
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)-beta1 levels in the non-HCC region. To define 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-beta1, 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-beta1 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-beta1 expression, and SOCS3 prevents this process.
最近，有报道称人类肝细胞癌（HCC）患者中存在DNA甲基化以及细胞因子信号转导抑制因子3（SOCS3）基因表达降低的情况。然而，SOCS3在体内HCC发展中的作用尚未明确。通过逆转录聚合酶链反应（RT-PCR）分析和蛋白质免疫印迹法，我们证实HCC患者中SOCS3表达降低。然而，SOCS3表达降低不仅发生在HCC中，也出现在非肿瘤区域，并且随着纤维化程度的增加，这种降低更为明显。此外，在非HCC区域，SOCS3水平与转录信号转导子和激活子3（STAT3）的激活以及转化生长因子（TGF）-β1水平呈负相关。为了确定SOCS3沉默/STAT3过度激活以及肝纤维化的分子后果，我们检测了肝脏特异性SOCS3缺陷小鼠。我们发现肝脏中SOCS3缺失导致STAT3过度激活，并促进刀豆蛋白A和化学物质诱导的肝纤维化。纤维化介质TGF-β1的表达通过SOCS3基因缺失而增强，但在体内和体外均被显性负性STAT3或SOCS3的过表达所抑制。这些数据表明TGF-β1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，我们目前的研究揭示了SOCS3和STAT3在HCC发展中的新作用：除了先前已确定的致癌潜能外，STAT3通过上调TGF-β1表达增强肝纤维化，而SOCS3可阻止这一过程。
