Oncotarget

Research Papers:

CCL2-CCR2 axis promotes metastasis of nasopharyngeal carcinoma by activating ERK1/2-MMP2/9 pathway

Jing Yang, Xing Lv, Jinna Chen, Changqing Xie, Weixiong Xia, Chen Jiang, Tingting Zeng, Yanfang Ye, Liangru Ke, Yahui Yu, Hu Liang, Xin-Yuan Guan, Xiang Guo and Yanqun Xiang _

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Oncotarget. 2016; 7:15632-15647. https://doi.org/10.18632/oncotarget.6695

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Abstract

Jing Yang1,2,*, Xing Lv1,2,*, Jinna Chen3,*, Changqing Xie4, Weixiong Xia1,2, Chen Jiang3, Tingting Zeng1,2, Yanfang Ye1,2, Liangru Ke1,2, Yahui Yu1,2, Hu Liang1,2, Xin-Yuan Guan1,3, Xiang Guo1,2, Yanqun Xiang1,2

1State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China

2Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center, Guangzhou, China

3Department of Clinical Oncology, Hong Kong University, Hong Kong, China

4Internal Medicine Residency Program, Vidant Medical Center, East Carolina University, Greenville, NC, USA

*These authors contributed equally to this work

Correspondence to:

Yanqun Xiang, e-mail: xiangyq@sysucc.org.cn

Xin-Yuan Guan, e-mail: xyguan@hkucc.hku.hk

Xiang Guo, e-mail: guoxiang@sysucc.org.cn

Keywords: CCL2/CCR2, nasopharyngeal carcinoma, metastasis, MMP2/9, ERK1/2

Received: August 17, 2015     Accepted: November 16, 2015     Published: December 20, 2015

ABSTRACT

Distant metastasis remains the major failure of nasopharyngeal carcinoma (NPC). In this study, the roles of chemokine C-C motif ligand 2 (CCL2), and its receptor chemokine C-C motif receptor type 2 (CCR2) on NPC metastasis were investigated. Serum CCL2 and CCL2/CCR2 expression level were remarkably increased in NPC patients compared to non-tumor patients by ELISA and IHC analyses. High expressions of CCL2/CCR2 were significantly associated with NPC metastasis and poor overall survival (OS). High expression of CCR2 is an independent adverse prognostic factor of OS and distant metastasis free survival (DMFS). Overexpressions of CCL2 and CCR2 were detected in high-metastatic NPC cell lines. Upregulating CCL2 and CCR2 respectively in low-metastatic NPC cell lines could promote cell migration and invasion, and exogenous CCL2 enhanced the motility in CCR2-overexpressing cells. On the other hand, downregulating CCL2 and CCR2 respectively in high-metastatic NPC cell lines by shRNA could decrease cell migration and invasion. However, exogenous CCL2 could not rescue the weaken ability of motility of CCR2-silencing cells. In nude mouse model, distant metastasis was significantly facilitated in either CCL2-overexpressing or CCR2-overexpressing groups, which was more obvious in CCR2-overexpressing group. Also, distant metastasis was considerably inhibited in either CCL2-silencing or CCR2-silencing groups. Dual overexpression of CCL2/CCR2 could activate extracellular signal-regulated kinase (ERK1/2) signaling pathway, which sequentially induced matrix metalloproteinase (MMP) 2 and 9 upregulations in the downstream. In conclusion, CCL2-CCR2 axis could promote NPC metastasis by activating ERK1/2-MMP2/9 pathway. This study helps to develop novel therapeutic targets for distant metastasis in NPC.


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