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

Huiying Ma,Qiang Gao,Pingping Xu,Chunmin Liang,Binbin Liu,Shichao Li,Shuang Zhou,Long Chen,Yihong Sun,Honglei Xiao,Jie Qin,Xinzhou Liu,Fei Wang,Lingling Gao

doi:10.18632/oncotarget.4484

Huiying Ma, Qiang Gao + Show 12 more

Open Access

https://doi.org/10.18632/oncotarget.4484

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Journal: Oncotarget	Publication Date: Jul 6, 2015
Citations: 51	License type: cc-by

Affiliation: Shanghai Medical College of Fudan University

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.

Highlights

With nearly one million new cases annually worldwide, gastric cancer (GC) is the fifth most common malignant disease and the second leading cause of cancer mortality
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 data show that CCR7-high significantly correlates with regional lymph node metastasis (P = 0.022), whereas there is no significant correlation between the level of CCR7 expression with patients’ age, gender, tumor differentiation, primary tumor parameters, distant metastasis or TNM stage

Summary

Introduction

With nearly one million new cases annually worldwide, gastric cancer (GC) is the fifth most common malignant disease and the second leading cause of cancer mortality. Despite improvements in diagnostic and treatment strategies, overall survival (OS) among GC patients remains poor, owing to high incidences of metastasis and recurrence. Chemokines and their receptors are key mediators of tumor invasion and metastasis [1,2,3,4]. CCR7 expression by tumor cells increases the likelihood of lymphatic invasion and lymph node metastasis and correlates with metastasis in breast cancer, squamous cell carcinoma of the head and neck, and colon cancer [6,7,8,9]. There is no direct evidence to explain how chemokine receptors mediate tumor cell invasion and metastasis

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