Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 16, Issue 14, Pages 2542-2558Publisher
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.45446
Keywords
HCC; CAFs; EMT; TG2; IL-6/IL6R/STAT3 axis
Categories
Funding
- National 13th Five-Year Science and Technology Plan Major Projects of China [2017ZX10203205]
- National Key RD Plan [2017YFA0104304]
- National Natural Science Foundation of China [81702393, 81770648, 81670601, 81570593, 81802897]
- Key Scientific and Technological Projects of Guangdong Province [2015B020226004, 2015A030312013, 2017A030311034]
- Guangdong Natural Science Foundation [2018A030313259]
- Science and Technology Planning Project of Guangdong Province [2017B030314027, 2017B020209004, 20169013]
- Science and Technology Planning Project of Guangzhou [2014Y2-00200, 2014Y2-00544, 201604020001, 201508020262, 201400000001-3]
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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.
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