CCR4 promotes metastasis via ERK/NF-κB/MMP13 pathway and acts downstream of TNF-α in colorectal cancer

// Baochi Ou 1, 2, 3, * , Jingkun Zhao 1, 2, 3, * , Shaopei Guan 1, 2, 3, * , Hao Feng 2, 4 , Xiongzhi Wangpu 1, 2 , Congcong Zhu 1, 2, 3 , Yaping Zong 1, 2 , Junjun Ma 1, 2 , Jing Sun 1, 2 , Xiaohui Shen 1 , Minhua Zheng 1, 2, 3 , Aiguo Lu 1, 2, 3 1 Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China 2 Shanghai Minimally Invasive Surgery Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China 3 Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China 4 Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, 81377 Munich, Germany * These authors contributed equally to this work Correspondence to: Aiguo Lu, email: weichuang_lu@163.com Minhua Zheng, email: minghua_zhen@yeah.net Xiaohui Shen, email: xhshendoc@yeah.net Keywords: CCR4, colorectal cancer, metastasis, MMP13, TNF-α Received: March 28, 2016      Accepted: June 09, 2016      Published: June 23, 2016 ABSTRACT Chemokines and chemokine receptors are causally involved in the metastasis of human malignancies. As a crucial chemokine receptor for mediating immune homeostasis, however, the role of CCR4 in colorectal cancer (CRC) remains unknown. In this study, we found that high expression of CCR4 in CRC tissues was correlated with shorter overall survival and disease free survival. In vitro and in vivo experiments revealed that silencing CCR4 attenuated the invasion and metastasis of CRC cells, whereas ectopic overexpression of CCR4 contributed to the forced metastasis of these cells. We further demonstrated that matrix metalloproteinase 13 (MMP13) played an important role in CCR4-mediated cancer cell invasion, which is up-regulated by ERK/NF-κB signaling. Positive correlation between CCR4 and MMP13 expression was also observed in CRC tissues. Moreover, our investigations showed that the level of CCR4 could be induced by TNF-α dependent of NF-κB activation in CRC cells. CCR4 might be implicated in TNF-α-regulated cancer cells metastasis. Combination of CCR4 and TNF-α is a more powerful prognostic marker for CRC patients. These findings suggest that CCR4 facilitates metastasis through ERK/NF-κB/MMP13 signaling and acts as a downstream target of TNF-α. CCR4 inhibition may be a promising therapeutic option for suppressing CRC metastasis.