M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma |
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| Authors: | Dalong Sun Tiancheng Luo Pingping Dong Ningping Zhang Jing Chen Shuncai Zhang Ling Dong Harry L. A. Janssen Si Zhang |
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| Affiliation: | 1. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China;2. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China Shanghai Institute of Liver Disease, Shanghai, China;3. Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong, China;4. Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China;5. Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada;6. NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China |
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| Abstract: | Tumor-associated macrophages (TAMs) have been considered as a major component of the tumor microenvironment. However, the crosstalk between M2-polarized tumor-associated macrophages (M2-TAMs) and intrahepatic cholangiocarcinoma (ICC) remains undetermined. In the present study, we aimed to clarify the role of M2-TAMs in ICC and the underlying mechanism. The in vitro assay demonstrated M2-TAMs promoted epithelial-mesenchymal transition (EMT) of ICC cells, resulting in enhanced cell invasion and metastasis ability. Moreover, M2-TAMs modulated the microenvironment of ICC by increasing the secretion of cytokines (GM-CSF, tumor necrosis factor-α [TNF-α], ICAM-1, interleukin-6 [IL-6], etc) and chemokines (CCL1, CCL3, etc). In addition, p-AKT (Ser473) and p-PRAS40 (Thr246) were upregulated in ICC cells when cocultured with M2-TAMs or treated with M2-TAMs secreted core cytokines (GM-CSF, TNF-α, ICAM-1, and IL-6). Consistently, AKT3 silencing (but not AKT1 silencing and AKT2 silencing) markedly inhibited phosphorylation of AKT and PRAS40 of ICC cells and inhibited the EMT process when cocultured with M2-TAMs. Taken together, the current data indicated that M2-TAMs promoted ICC cells EMT, partially through increasing secretion of cytokines and chemokines, thus modulating the microenvironment and activating the AKT3/PRAS40 signaling pathway. |
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| Keywords: | AKT3 cytokines epithelial-mesenchymal transition intrahepatic cholangiocarcinoma tumor microenvironment tumor-associated macrophages |
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