CCR7 enhances TGF-β1-induced epithelial-mesenchymal transition and is associated with lymph node metastasis and poor overall survival in gastric cancer

Abstract

// Huiying Ma 1, * , Lingling Gao 1, * , Shichao Li 2, * , Jie Qin 1 , Long Chen 1 , Xinzhou Liu 1 , Pingping Xu 2 , Fei Wang 1 , Honglei Xiao 1 , Shuang Zhou 1, 4 , Qiang Gao 3 , Binbin Liu 3 , Yihong Sun 2 , Chunmin Liang 1 1 Lab of Tumor Immunology, Department of Anatomy and Histology & Embryology, Shanghai Medical College of Fudan University, Shanghai, P. R. China 2 The General Surgery Department of Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, P. R. China 3 The Liver Cancer Institute of Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, P. R. China 4 The Department of Anatomy and Histology & Embryology, Tongji University School of Medicine, Shanghai, P. R. China * These authors have contributed equally to this work Correspondence to: Chunmin Liang, e-mail: cmliang@fudan.edu.cn Yihong Sun, e-mail: sun.yihong@zs-hospital.sh.cn Keywords: gastric cancer, CCR7, epithelial-mesenchymal transition, TGF-β1, co-stimulatory Received: March 12, 2015      Accepted: June 25, 2015      Published: July 06, 2015 ABSTRACT CCR7 is a G protein-coupled chemokine receptor. In this study, we used immunohistochemistry with tissue microarrays to measure CCR7 expression in tumor specimens from 122 patients with gastric cancer. We show that CCR7 expression is associated with lymph node metastasis ( P = 0.022) and overall survival (OS; P = 0.025), and is an independent factor associated with poorer overall survival ( P = 0.032). The CCR7 mechanism was predicted based on bioinformatic analysis and verified in gastric cancer cell lines and primary tumor samples. The data show that CCR7 contributes to TGF-β1-induced epithelial-mesenchymal transition (EMT) and that the effects of TGF-β1 are inhibited by a CCR7 neutralizing antibody or a NF-κB inhibitor. Increased TGF-β1 expression was accompanied by nuclear localization of NF-κB-p65 and higher levels of the mesenchymal marker vimentin in human gastric cancer samples. We conclude that the CCR7 axis mediates TGF-β1-induced EMT via crosstalk with NF-κB signaling, facilitating lymph node metastasis and poorer overall survival in patients with gastric cancer. These findings suggest CCR7 is a novel prognostic indicator and a potential target for gastric cancer therapy.