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Loss of SOCS3 in the Liver Promotes Fibrosis by Enhancing STAT3

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Loss of SOCS3 in the Liver Promotes Fibrosis by Enhancing STAT3 Oncogene (2006) 25, 2520–2530 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-b1 production H Ogata1,2, T Chinen1, T Yoshida1,3, I Kinjyo1, G Takaesu1, H Shiraishi1, M Iida2, T Kobayashi1 and A Yoshimura1 1Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Fukuoka, Japan and 2Department of Medicine and Clinical Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan Recently, DNA methylation and reduced expression of the Introduction suppressor of the cytokine signaling-3 (SOCS3) gene in human hepatocellular carcinoma (HCC) patients have Most hepatocellular carcinomas (HCCs) develop as a been reported. However, the roles of SOCS3 in HCC result of liver cirrhosis and advanced fibrosis. IL-6 has development in vivo have not been clarified. Using RT– been implicated in the promotion of inflammation, PCR analysis and Western blotting, we confirmed that fibrosis, and carcinogenesis in the liver. This is because SOCS3 expression was reduced in HCC patients. high levels of IL-6 induce hepatic inflammation, However, reduced expression of SOCS3 occurred not collagen synthesis, tissue inhibitor of metalloprotei- only in HCC but also in nontumor regions, and this nase-1 (TIMP1) expression, and early transition of reduction was stronger as the fibrosis grade increased. stellate cells (also called Ito cells and lipocytes) into Furthermore, SOCS3 levels were inversely correlated with myofibroblasts in mice (Choi et al., 1994). Hyperactiva- signal transducers and activators of transcription-3 tion of the signal transducers and activators of (STAT3) activation as well as transforming growth factor transcription-3 (STAT3), which is a downstreamof (TGF)-b1 levels in the non-HCC region. To define the IL-6/gp130, has been reported in HCC (Yoshikawa molecular consequences of SOCS3 silencing/STAT3 et al., 2001). STAT3 is believed to contribute to cell hyperactivation and liver fibrosis, we examined liver- proliferation and antiapoptosis by inducing c-myc, specific SOCS3-deficient mice. We demonstrated that cyclin-D1, and Bcl-XL and, therefore, functions as an SOCS3 deletion in the liver resulted in hyperactivation of oncogene (Bromberg et al., 1999; Bromberg and STAT3 and promoted ConA-and chemical-induced liver Darnell, 2000). Recently, STAT3 was shown to induce fibrosis. The expression of TGF-b1, a mediator of fibrosis, the vascular endothelial growth factor (VEGF), which was enhanced by SOCS3 gene deletion, but suppressed by contributes to tumor-associated angiogenesis. Further- the overexpression of a dominant-negative STAT3 or more, STAT3 suppresses the tumor expression of SOCS3 both in vivo and in vitro. These data suggest that proinflammatory cytokines and chemokines, resulting TGF-b1 is a target gene of STAT3 and could be one of the in the reduced activation of antitumor immunity (Wang mechanisms for enhanced fibrosis in SOCS3-deficient et al., 2004). Therefore, STAT3 is deeply involved in mice. Thus, our present study provides a novel role of HCC development by multiple mechanisms (Wei et al., SOCS3 and STAT3 in HCC development: in addition to 2003). STAT3 is activated not only by IL-6 and related the previously characterized oncogenic potentials, STAT3 cytokines, but also by direct interaction with the enhances hepatic fibrosis through the upregulation of hepatitis C virus (HCV) core protein in the liver TGF-b1 expression, and SOCS3 prevents this process. (Yoshida et al., 2002). Oncogene (2006) 25, 2520–2530. doi:10.1038/sj.onc.1209281; Cytokines, including IL-6, activate the Janus kinase published online 13 February 2006 (JAK)/STAT signaling pathway, which plays a vital role in various conditions, including immune reaction, cell Keywords: SOCS; STAT; TGF-b1; liver fibrosis growth, and differentiation. Cytokine signaling is strictly regulated by suppressor of the cytokine signaling (SOCS) family proteins. Among them, SOCS1 is relatively specific to STAT1, and SOCS3 to STAT3 (Kinjyo et al., 2002; Croker et al., 2003; Yasukawa et al., Correspondence: Dr A Yoshimura, Division of Molecular and Cellular 2003). SOCS1 inhibits JAK activation through its N- Immunology, Medical Institute of Bioregulation, Kyushu University, terminal kinase inhibitory region (KIR) by direct 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. binding to the activation loop of JAKs, while SOCS3 E-mail: [email protected] inhibits JAK kinase by binding to the cytokine receptors 3Current address: Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume 830-0011, Japan. through its SH2 domain. Furthermore, the SOCS Received 30 August 2005; revised 5 October 2005; accepted 25 October box, another domain in SOCS proteins, is able to 2005; published online 13 February 2006 interact with Elongins B and C and couples the SH2 SOCS3 regulates hepatic fibrosis and TGF-b1 H Ogata et al 2521 domain-binding proteins to the ubiquitin–proteasome Results pathway (Kamura et al., 1998; Kamizono et al., 2001). Therefore, SOCS1 and SOCS3 inhibit cytokine signaling Correlation between STAT3 activation, SOCS by suppressing JAK kinase activity and promoting the expression, and fibrosis in human HCC degradation of the activated cytokine receptor complex. We investigated the correlation between STAT3 activa- SOCS1 induction is restricted to interferons and some tion and the expression levels of SOCSs in HCC and other cytokines, while SOCS3 is induced by a variety of noncancerous tissues in human patients. As reported, we stimuli, such as interleukins, interferons, and TNFa confirmed that both SOCS1 and SOCS3 mRNA levels (Bode et al., 1999; Yasukawa et al., 2003; Kamio et al., were lower in the HCC region than in the nontumor 2004). However, since binding of the SH2 domain region (data not shown). However, we noticed that the of SOCS3 is relatively specific to the receptors for SOCS3 expression levels in the non-HCC region were STAT3-activating cytokines, such as IL-6, G-CSF, variable and often very low in samples with severe and leptin, the effect of SOCS3 may be relatively fibrosis. Therefore, we compared the correlation be- restricted to STAT3 (Croker et al., 2003, 2004; Mori tween fibrosis and STAT3 activation and SOCS3 et al., 2004). expression in non-HCC regions. We also examined the In connection with SOCS and HCC, the SOCS1 gene levels of TGF-b1, an essential mediator of fibrosis has been implicated as an antioncogene for HCC (Nakamura et al., 2000). The progression of liver development. Yoshikawa et al. (2001) reported aberrant fibrosis was classified into four stages, fromF1 to F4, methylation in the CpG island of SOCS1 that correlated as judged by histological examination (Bedossa and with its transcriptional silencing in HCC cell lines. In support of this, a recent experiment has shown that SOCS1 heterozygous mice are hypersensitive to diethyl- nitrosamine (DEN)-induced hepatocarcinogenesis (Yoshida et al., 2004). A simple explanation is that STAT3 hyperactivation is the result of reduced expres- sion of SOCS1 by DNA methylation, which leads to hyperproliferation and antiapoptosis of hepatocarcino- ma cells. However, the effect of SOCS3 deletion on STAT3 hyperactivation has not been demonstrated in vivo, and, as we reported, STAT3 is mostly regulated by SOCS3 rather than SOCS1 (Kimura et al., 2004; Mori et al., 2004). Recently, reduced expression of SOCS3 and aberrant methylation in the CpG island of the SOCS3 locus in HCC patient samples and cell lines have been reported (Niwa et al., 2005). These researchers also reported that SOCS3 negatively regulates cell growth and cell motility by inhibiting STAT3 and FAK signalings in cultured HCC cell lines. However, the effect of SOCS3 gene silencing in the liver in HCC development and STAT3 activation has not been established in vivo. In this study, using RT–PCR and Western blotting, we confirmed that the expression of SOCS3 was reduced in the liver of human HCC patients. However, the reduction of SOCS3 expression was observed not only in HCC regions but also in non-HCC regions. SOCS3 expression levels were inversely correlated with STAT3 activation and fibrosis. Thus, we investigated the role of SOCS3 in liver fibrosis using liver-specific SOCS3-deficient mice. We demonstrated that STAT3 hyperactivation promoted chemical compound- and concanavalin-A (ConA)-induced liver fibrosis. Part of this mechanism is explained by the transcrip- Figure 1 Enhanced STAT3 activation and reduced expression tional induction of transforming growth factor levels of SOCS3 in human liver tissues. (a, b) Relative expression levels of the TGF-b1(a) and SOCS3 (b) mRNA in each fibrosis (F) (TGF)-b1, an essential mediator of fibrosis, through stage and HCC, as determined by real-time RT–PCR. N ¼ 5 for STAT3. These findings suggest that SOCS3 contributes each stage. (c, d) Western blot analysis of phosphorylated STAT3 to the suppression of HCC development by protecting (pY-STAT3) and SOCS3 in human liver lysates. Data are the liver cells against hepatic fibrosis mediated by representative of three separate experiments. In (d), STAT3 phosphorylation levels are quantified by densitometry and normal- TGF-b1. Our study also provides a basis for the ized to STAT3 levels. The data are shown as the mean7s.e.m. therapeutic potential of liver cirrhosis/HCC by STAT3 (number of each F stage ¼ 5), *Po0.05; **Po0.01; NS, no antagonists. significant difference. Oncogene SOCS3 regulates hepatic fibrosis and TGF-b1 H Ogata et al 2522 Poynard, 1996). As shown in Figure 1a, the TGF-b1 gene deletion was specific to the liver and did not occur mRNA levels, determined by real-time RT–PCR, were in other tissues, including the brain, heart, kidney, fat, well correlated with the fibrosis grade. As expected, the and muscle (Figure 2c). The AdCre-mediated SOCS3 SOCS3 mRNA (Figure 1b) and protein (Figure 1c) deletion in the liver continued for more than 7 weeks levels, as determined by Western blotting, decreased as (Figure 2c).
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