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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01741

Regulatory T cells promote overexpression of Lgr5 on gastric cancer cells via TGF-beta1 and confer poor prognosis in gastric cancer

Xiaosun Liu1, Xianke Lin1, Ying Mei1, Sabir Ahmad1, Chongxian Yan1, Hailong Jin1, Hang Yu1, Chao Chen1, Caizhao Lin1 and  Jiren Yu1*
  • 1First Affiliated Hospital, College of Medicine, Zhejiang University, China

Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.

Keywords: LGR5 protein, human, Stomach Neoplasms, T-Lymphocytes, Regulatory, Transforming Growth Factor beta1, Immune microenviroment

Received: 07 Apr 2019; Accepted: 10 Jul 2019.

Edited by:

Fang-Ping Huang, The University of Hong Kong, Hong Kong

Reviewed by:

Zong Sheng Guo, School of Medicine, University of Pittsburgh, United States
Frederique VEGRAN, INSERM U1231 Lipides, Nutrition, Cancer (LNC), France  

Copyright: © 2019 Liu, Lin, Mei, Ahmad, Yan, Jin, Yu, Chen, Lin and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jiren Yu, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang Province, China, yujr0909@zju.edu.cn