IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment.

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.

Zheng X ，Xu M ，Yao B ，Wang C ，Jia Y ，Liu Q ... -  《-》

Cancer-associated Fibroblasts induce epithelial-mesenchymal transition via the Transglutaminase 2-dependent IL-6/IL6R/STAT3 axis in Hepatocellular Carcinoma.

Cancer-associated fibroblasts (CAFs) play crucial roles in enhancing cell survival, proliferation, invasion, and metastasis. We previously showed that hepatocellular carcinoma-derived CAFs (H-CAFs) promoted proliferation of hepatocellular carcinoma (HCC) cells. This study aimed to further explore the role of CAFs in HCC epithelial-mesenchymal transition (EMT) and the underlying mechanism. High CAF density was significantly associated with liver cirrhosis, inferior clinicopathologic characteristics, elevated EMT-associated markers, and poorer survival in human HCC. Within HCC cells, EMT was induced after co-culture with H-CAFs. Secretomic analysis showed that IL-6 and HGF were the key EMT-stimulating cytokines secreted by H-CAFs. Proteomic analysis revealed that TG2 was significantly upregulated in HCC cells with EMT phenotypes. Overexpression of TG2 promoted EMT of HCC cells, and knockdown of TG2 remarkably attenuated the H-CAF-induced EMT. Furthermore, during EMT, TG2 expression was enhanced after HCC cells were stimulated by IL-6, but not HGF. Inhibition of the IL-6/STAT3 signaling decreased TG2 expression. The principal TG2 transcription control element and a potential STAT3 binding site were identified using promoter analysis. Hence, H-CAFs facilitates HCC cells EMT mediated by IL-6, which in turn activates IL-6/IL6R/STAT3 axis to promote TG2 expression.

Jia C ，Wang G ，Wang T ，Fu B ，Zhang Y ，Huang L ，Deng Y ，Chen G ，Wu X ，Chen J ，Pan Y ，Tai Y ，Liang J ，Li X ，Hu K ，Xie B ，Li S ，Yang Y ，Chen G ，Zhang Q ，Liu W ... -  《International Journal of Biological Sciences》

TIMP-1 activated carcinoma-associated fibroblasts inhibit tumor apoptosis by activating SDF1/CXCR4 signaling in hepatocellular carcinoma.

Song T ，Dou C ，Jia Y ，Tu K ，Zheng X ... -  《Oncotarget》

Histone acetyltransferase PCAF accelerates apoptosis by repressing a GLI1/BCL2/BAX axis in hepatocellular carcinoma.

Gai X ，Tu K ，Li C ，Lu Z ，Roberts LR ，Zheng X ... -  《Cell Death & Disease》

IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma.

Gu FM ，Li QL ，Gao Q ，Jiang JH ，Zhu K ，Huang XY ，Pan JF ，Yan J ，Hu JH ，Wang Z ，Dai Z ，Fan J ，Zhou J ... -  《Molecular Cancer》