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M2‐polarized tumor‐associated macrophages promote epithelial‐mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma
Author(s) -
Sun Dalong,
Luo Tiancheng,
Dong Pingping,
Zhang Ningping,
Chen Jing,
Zhang Shuncai,
Dong Ling,
Janssen Harry L. A.,
Zhang Si
Publication year - 2020
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29514
Subject(s) - tumor microenvironment , cancer research , epithelial–mesenchymal transition , protein kinase b , gene silencing , chemistry , proinflammatory cytokine , tumor necrosis factor alpha , chemokine , signal transduction , downregulation and upregulation , inflammation , microbiology and biotechnology , biology , immunology , biochemistry , tumor cells , gene
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.