SHH/GLI2-TGF-β1 feedback loop between cancer cells and tumor-associated macrophages maintains epithelial-mesenchymal transition and endoplasmic reticulum homeostasis in cholangiocarcinoma

作者：Zuxiao Chen, Haiyan Li, Zongyan Li, Shaoyi Chen, Xiaoming Huang, Zheyu Zheng, Xiangjun Qian, Lei Zhang, Guojie Long, Jiancong Xie, Qian Wang, Weidong Pan, Dawei Zhang · 发表于：Pharmacological Research · 年份：2022 · DOI：10.1016/j.phrs.2022.106564 · 被引用次数：47 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Immune cells in cancer、Ferroptosis and cancer prognosis

BACKGROUND: Tumor-associated macrophages (TAMs) play a dual role in tumors. However, the factors which drive the function of TAMs in cholangiocarcinoma remain largely undefined. METHODS: SHH signaling pathway and endoplasmic reticulum stress (ERS) indicators were detected in clinical tissues and cholangiocarcinoma cell lines. TAMs were co-cultured with cholangiocarcinoma cells under conditions of hypoxia/normoxia. Polarized TAMs were counted by flow cytometry, and TGF-β1 levels in cell supernatants were detected by ELISA. The effects of glioma-associated oncogene GLI2 on TAMs themselves and cholangiocarcinoma cells were examined by conducting interference and overexpression assays. RESULTS: The SHH signaling pathway and ERS were both activated in tumor tissues or tumor cell lines under conditions of hypoxia. In co-culture experiments, the presence of cholangiocarcinoma cells increased the proportion of M2-polarized TAMs and the secretion of TGF-β1 by TAMs, while knockdown of SHH expression reversed those increases. Overexpression of GLI2 in TAMS or stimulation of TAMS with Hh-Ag1.5 increased their levels of TGF-β1 expression. Furthermore, under co-culture conditions, interference with GLI2 expression in TAMs reduced the tumor cell migration, invasion, and ER homeostasis induced by Hh-Ag1.5-pretreated TAMs. Under conditions of hypoxia, the presence of cholangiocarcinoma cells promoted the expression of GLI2 and TGF-β1 in Tams, and in turn, TAMs inhibited the apoptosis and prom...