M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma
M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma
复制标题
M2极化肿瘤相关巨噬细胞通过激活肝内胆管癌中的AKT3/PRAS40信号通路促进上皮间质转化
DOI：
10.1002/jcb.29514
复制
发表时间：
2019-11-06
影响因子：
4
通讯作者：
Zhang, Si
中科院分区：
文献类型：
--
作者：
Sun, Dalong;Luo, Tiancheng;Zhang, Si
肿瘤相关巨噬细胞（TAM）被认为是肿瘤微环境的主要组成部分。然而，M2 极化肿瘤相关巨噬细胞 (M2-TAM) 与肝内胆管癌 (ICC) 之间的串扰仍不清楚。在本研究中，我们旨在阐明 M2-TAM 在 ICC 中的作用及其潜在机制。体外实验表明，M2-TAMs 促进 ICC 细胞的上皮间质转化（EMT），从而增强细胞侵袭和转移能力。此外，M2-TAMs通过增加细胞因子（GM-CSF、肿瘤坏死因子-α [TNF-α]、ICAM-1、白介素-6 [IL-6]等）和趋化因子（CCL1、CCL3等）的分泌来调节ICC的微环境。此外，当与 M2-TAM 共培养或用 M2-TAM 分泌的核心细胞因子（GM-CSF、TNF-α、ICAM-1 和 IL-6）处理时，ICC 细胞中的 p-AKT (Ser473) 和 p-PRAS40 (Thr246) 上调。一致地，当与 M2-TAM 共培养时，AKT3 沉默（但不是 AKT1 沉默和 AKT2 沉默）显着抑制 ICC 细胞 AKT 和 PRAS40 的磷酸化，并抑制 EMT 过程。综上所述，目前的数据表明，M2-TAMs 促进 ICC 细胞 EMT，部分是通过增加细胞因子和趋化因子的分泌，从而调节微环境并激活 AKT3/PRAS40 信号通路。
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-alpha [TNF-alpha], 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-alpha, 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.