Cancer-associated Fibroblasts induce epithelial-mesenchymal transition <i>via</i> the Transglutaminase 2-dependent IL-6/IL6R/STAT3 axis in Hepatocellular Carcinoma
Changchang Jia, Guoying Wang, Tiantian Wang, Binsheng Fu, Yincai Zhang, Lei Huang, Yinan Deng, Guanzhong Chen, Xiaocai Wu, Jianning Chen, Yuhang Pan, Yan Tai, Jinliang Liang, Xuejiao Li, Kunhua Hu, Bo Xie, Sujun Li, Yang� Yang, Guihua Chen, Qi Zhang, Wei Liu
Abstract
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.