Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, China.
Front Immunol. 2019 Jul 30;10:1741. doi: 10.3389/fimmu.2019.01741. eCollection 2019.
The leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) is considered a cancer stem cell marker, and is often overexpressed in tumors. The interaction between Lgr5 and the immune-related tumor microenvironment is not completely understood. The aim of this study was to examine the role of Lgr5 in the microenvironment of gastric cancer (GC), and to explore possible immunological mechanisms influencing Lgr5 expression that are governed by regulatory T cells. Lgr5 expression was examined in 180 GC tumors by immunohistochemistry, and in 80 pairs of GC tumors for analysis of Th1/Th2 cytokines by ELISA. In addition, SGC7901 cells were co-cultured with patient-derived Tregs, varying concentrations of TGF-β1, TGF-β1 neutralizing antibody, or TGF-β receptor inhibitor SB431542, and Lgr5 and β-catenin expression were examined by qRT-PCR and western blot. In this study, an immunosuppressive microenvironment was associated with high Lgr5 expression in GC. Furthermore, Lgr5 expression was up-regulated in GC cells co-cultured with Tregs or treated with exogenous TGF-β1. This up-regulation was partially inhibited by the TGF-β1 neutralizing antibody, or TGF-β1 receptor antagonist SB431542. β-catenin was up-regulated with high Lgr5 expression induced by exogenous TGF-β1, and this up-regulation was inhibited by SB431542. An increased number of Tregs and high Lgr5 expression in GC tissues were significantly associated with low overall survival. Tregs promoted increased Lgr5 expression in GC cells via TGF-β1 and TGF-β1 signaling pathway, which may involve activation of the Wnt signaling pathway. High Lgr5 expression via TGF-β confer poor prognosis in gastric cancer.
富含亮氨酸重复序列的 G 蛋白偶联受体 5（Lgr5）被认为是癌症干细胞标志物，在肿瘤中常过表达。Lgr5 与免疫相关的肿瘤微环境之间的相互作用尚未完全阐明。本研究旨在探讨 Lgr5 在胃癌（GC）微环境中的作用，并探索可能受调节性 T 细胞（Treg）调控的影响 Lgr5 表达的免疫学机制。通过免疫组化检测了 180 例 GC 肿瘤中 Lgr5 的表达，并通过 ELISA 分析了 80 对 GC 肿瘤中 Th1/Th2 细胞因子的表达。此外，将 SGC7901 细胞与患者来源的 Treg 共培养，用不同浓度的 TGF-β1、TGF-β1 中和抗体或 TGF-β 受体抑制剂 SB431542 处理，通过 qRT-PCR 和 Western blot 检测 Lgr5 和 β-catenin 的表达。在本研究中，GC 中存在免疫抑制微环境与 Lgr5 高表达相关。此外，GC 细胞与 Treg 共培养或用外源性 TGF-β1 处理后，Lgr5 表达上调。TGF-β1 中和抗体或 TGF-β 受体拮抗剂 SB431542 部分抑制了这种上调。外源性 TGF-β1 诱导的 Lgr5 高表达上调了β-catenin，而 SB431542 抑制了这种上调。GC 组织中 Treg 增多和 Lgr5 高表达与总生存率降低显著相关。Treg 通过 TGF-β1 及其信号通路促进 GC 细胞中 Lgr5 的表达增加，这可能涉及 Wnt 信号通路的激活。TGF-β 介导的 Lgr5 高表达预示着胃癌预后不良。
