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

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.