M2‐polarized tumor‐associated macrophages promote epithelial‐mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma. Issue 4 (6th November 2019)

• Record Type: Journal Article
• Authors: Sun, Dalong; Luo, Tiancheng; Dong, Pingping; Zhang, Ningping; Chen, Jing; Zhang, Shuncai; Dong, Ling; Janssen, Harry L. A.; Zhang, Si
• Is Part Of: Journal of cellular biochemistry. Volume 121:Issue 4(2020)
• Page Start: 2828
• Page End: 2838
• Publication Date: 2019-11-06
• Subjects: AKT3 -- cytokines -- epithelial‐mesenchymal transition -- intrahepatic cholangiocarcinoma -- tumor microenvironment -- tumor‐associated macrophages; Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.29514
• Languages: English
• ISSNs: 0730-2312

Abstract

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. Abstract : The purpose of this study was to determine the role of M2‐polarized tumor‐associated macrophages (M2‐TAMs) in intrahepatic cholangiocarcinoma (ICC) and aimed to clarify the mechanism underlying the crosstalk between TAMs and ICC. Study data revealed that M2‐polarized TAMs mediated the secretion of cytokines, chemokines, thus modulated the microenvironment of ICC cells and facilitated the migration and invasion of ICC cells, partly via the AKT3/PRAS40 signaling pathway.