IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment.
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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DOI：
10.1016/j.cellsig.2016.06.009
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发表时间：
2016-09
影响因子：
4.8
通讯作者：
Xin Zheng;Meng Xu;B. Yao;Cong-xia Wang;Yuli Jia;Qingguang Liu
中科院分区：
文献类型：
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作者：
Xin Zheng;Meng Xu;B. Yao;Cong-xia Wang;Yuli Jia;Qingguang Liu
肿瘤微环境异常与肿瘤的发生和发展密切相关，其中癌相关成纤维细胞（cancer associated fibroblasts, CAFs）起着关键作用。IL-6/STAT3信号和TIMP-1均可调节肿瘤微环境中肿瘤细胞与CAFs之间的串扰，但其机制尚不清楚。在这里，我们发现IL-6/STAT3信号在HCC组织中异常激活，并与术后不良预后相关。体外实验证实，激活IL-6/STAT3通路直接通过磷酸化STATs （p-STAT3）结合TIMP-1启动子在Huh7细胞中增强TIMP-1的表达。此外，在HCC细胞中激活IL-6/STAT3通路可通过上调TIMP-1表达诱导正常肝成纤维细胞（LFs）向CAFs转化。体外和体内与CAFs共培养均能促进Huh7细胞的生长。最后，通过免疫共沉淀和免疫印迹评估，发现PCAF是一种众所周知的乙酰转移酶，可直接使细胞质STAT3蛋白乙酰化，并在Huh7细胞中负向调节TIMP-1的表达。总之，本研究表明，在HCC细胞与其邻近成纤维细胞之间存在一个正的IL-6/TIMP-1反馈回路控制着串扰。这里的数据还发现PCAF通过STAT3的乙酰化抑制TIMP-1的表达。综上所述，本研究表明，在肝癌细胞中，CAFs通过IL-6/STAT3/AKT通路促进肝癌细胞生长，而IL-6/STAT3通路驱动TIMP-1过表达通过激活LFs带来更多的CAFs。最后，PCAF可以通过使HCC细胞中的STAT3乙酰化来阻断这种正反馈。
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 CAFs 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 CAFs promoted HCC growth via IL-6/STAT3/AKT pathway and TIMP-1 over-expression driven by IL-6/STAT3 pathway in HCC cells brought in more CAFs through activating LFs. Finally, PCAF could block this positive feedback by acetylating STAT3 in HCC cells.