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

• Published in: International journal of biological sciences Vol. 16; no. 14; pp. 2542 - 2558
• Main Authors: Jia, Changchang, Wang, Guoying, Wang, Tiantian, Fu, Binsheng, Zhang, Yincai, Huang, Lei, Deng, Yinan, Chen, Guanzhong, Wu, Xiaocai, Chen, Jianning, Pan, Yuhang, Tai, Yan, Liang, Jinliang, Li, Xuejiao, Hu, Kunhua, Xie, Bo, Li, Sujun, Yang, Yang, Chen, Guihua, Zhang, Qi, Liu, Wei
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2020; Ivyspring International Publisher
• Subjects: Binding sites; Cancer; Cell culture; Cell proliferation; Cell survival; Cirrhosis; Cytokines; Fibroblasts; Growth factors; Hepatocellular carcinoma; Infections; Interleukin 6; Interleukin 6 receptors; Liver cancer; Liver cirrhosis; Medical prognosis; Mesenchyme; Metastases; Metastasis; Morphology; Phenotypes; Proteomics; Research Paper; Stat3 protein; Survival; Transcription; Transglutaminase 2; Wound healing; HCC; CAFs; EMT; TG2; IL-6/IL6R/STAT3 axis
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.45446

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.