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首页> 外文期刊>Cellular Signalling >IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment
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IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment

机译：IL-6 / STAT3轴通过上调TIMP-1来启动CAF，TIMP-1在肝癌微环境中被PCAF诱导的STAT3乙酰化而减弱

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摘要

Aberrant tumor microenvironment is involved closely in tumor initiation and progression, in which cancer associated fibroblasts (CAFs) play a pivotal role. Both IL-6/STAT3 signaling and TIMP-1 have been found to modulate the crosstalk between tumor cells and CAFs in tumor microenvironment, however, the underlying mechanism remains unclear. Here, we showed that IL-6/STAT3 signaling was activated aberrantly in HCC tissues and correlated with poor post-surgical outcome. The in vitro experiments confirmed that activation of IL-6/STAT3 pathway enhanced TIMP-1 expression directly via phosphorylated STATs (p-STAT3)-binding with TIMP-1 promoter in Huh7 cells. Furthermore, activation of IL-6/STAT3 pathway in HCC cells was shown to induce the transformation from normal liver fibroblasts (LFs) to CAF5 via up-regulating TIMP-1 expression. Co-culture with CAFs promoted the growth of Huh7 cells both in vitro and in vivo. Finally, by co-Immunoprecipitation and immunoblotting assessments, PCAF, a well-known acetyltransferase, was revealed to acetylate cytoplasmic STAT3 protein directly and regulate TIMP-1 expression negatively in Huh7 cells. In summary, this investigation indicated that there was a positive IL-6/TIMP-1 feedback loop controlling the crosstalk between HCC cells and its neighbouring fibroblasts. The data here also identified that PCAF repressed TIMP-1 expression via acetylation of STAT3. In conclusion, this investigation demonstrated that CAF5 promoted HCC growth via IL-6/STAT3/AKT pathway and TIMP1 over-expression driven by IL-6/STAT3 pathway in HCC cells brought in more CAF5 through activating LFs. Finally, PCAF could block this positive feedback by acetylating STAT3 in HCC cells. (C) 2016 Elsevier Inc. All rights reserved.
机译：异常的肿瘤微环境与肿瘤的发生和发展密切相关，其中癌症相关的成纤维细胞（CAF）起着举足轻重的作用。已发现IL-6 / STAT3信号传导和TIMP-1均可调节肿瘤微环境中肿瘤细胞与CAF之间的串扰，但是，其潜在机制仍不清楚。在这里，我们表明，IL-6 / STAT3信号在肝癌组织中异常激活，并且与不良的术后结果相关。体外实验证实，IL-6 / STAT3途径的激活直接通过与TIMP-1启动子结合的磷酸化STAT（p-STAT3）结合，增强了TIMP-1的表达。此外，HCC细胞中IL-6 / STAT3途径的激活可通过上调TIMP-1表达诱导从正常肝成纤维细胞（LFs）到CAF5的转化。与CAF的共培养促进了Huh7细胞的体外和体内生长。最后，通过共同免疫沉淀和免疫印迹评估，发现了一种众所周知的乙酰基转移酶PCAF，可以直接乙酰化细胞质STAT3蛋白，并在Huh7细胞中负调控TIMP-1的表达。总而言之，这项研究表明存在一个阳性的IL-6 / TIMP-1反馈环，可控制HCC细胞与其相邻成纤维细胞之间的串扰。此处的数据还确定了PCAF通过STAT3的乙酰化抑制了TIMP-1表达。总之，这项研究表明，CAF5通过IL-6 / STAT3 / AKT途径促进了HCC的生长，并且IL-6 / STAT3途径驱动的TIMP1过表达在HCC细胞中通过激活LF引入了更多的CAF5。最后，PCAF可以通过乙酰化HCC细胞中的STAT3来阻断这种正反馈。 （C）2016 Elsevier Inc.保留所有权利。

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