M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma

  • J Cell Biochem. 2020 Apr;121(4):2828-2838. doi: 10.1002/jcb.29514.
Dalong Sun  1  2  3 ,  Tiancheng Luo  1  2 ,  Pingping Dong  4 ,  Ningping Zhang  1  2 ,  Jing Chen  5 ,  Shuncai Zhang  1  2 ,  Ling Dong  1  2 ,  Harry L A Janssen  6 ,  Si Zhang  7
Affiliations
  • 1. Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2. Shanghai Institute of Liver Disease, Shanghai, China.
  • 3. Department of Gastroenterology and Hepatology, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China.
  • 4. Department of Surgery, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 5. Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 6. Toronto Center for Liver Disease, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada.
  • 7. NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, China.
PMID: 31692069 DOI: 10.1002/jcb.29514
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.

Keywords
AKT3; cytokines; epithelial-mesenchymal transition; intrahepatic cholangiocarcinoma; tumor microenvironment; tumor-associated macrophages.
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