Int J Biol Sci 2020; 16(14):2542-2558. doi:10.7150/ijbs.45446

Research Paper

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

Changchang Jia1,2*, Guoying Wang2,3*, Tiantian Wang4*, Binsheng Fu2,3, Yincai Zhang2,3, Lei Huang2, Yinan Deng2,3, Guanzhong Chen2,3, Xiaocai Wu2,3, Jianning Chen5, Yuhang Pan5, Yan Tai2, Jinliang Liang2, Xuejiao Li2, Kunhua Hu6, Bo Xie6, Sujun Li7, Yang Yang2,3, Guihua Chen2,3✉, Qi Zhang1,2✉, Wei Liu2✉

1. Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
2. Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
3. Department of Hepatic Surgery and Liver transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangzhou, China.
4. Department of medical oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
5. Department of pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
6. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
7. School of Informatics, computing and engineering, Indiana University, Bloomington, IN, USA.
*These authors contributed equally to this work.

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Citation:
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. Cancer-associated Fibroblasts induce epithelial-mesenchymal transition via the Transglutaminase 2-dependent IL-6/IL6R/STAT3 axis in Hepatocellular Carcinoma. Int J Biol Sci 2020; 16(14):2542-2558. doi:10.7150/ijbs.45446. Available from http://www.ijbs.com/v16p2542.htm

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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.

Keywords: HCC, CAFs, EMT, TG2, IL-6/IL6R/STAT3 axis