Oncotarget

Research Papers:

CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms

Gang Xiao _, Xiumin Wang, Jinglong Wang, Lidong Zu, Guangcun Cheng, Mingang Hao, Xueqing Sun, Yunjing Xue, Jinsong Lu and Jianhua Wang

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Oncotarget. 2015; 6:14165-14178. https://doi.org/10.18632/oncotarget.3690

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Abstract

Gang Xiao1, Xiumin Wang1, Jinglong Wang1, Lidong Zu1, Guangcun Cheng1, Mingang Hao1, Xueqing Sun1, Yunjing Xue1, Jinsong Lu2 and Jianhua Wang3

1 Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2 Comprehensive Breast Health Center, Renji Hospital, Shanghai, China

3 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China

Correspondence to:

Jianhua Wang, email:

Jinsong Lu, email:

Keywords: CXCL16/CXCR6, breast cancer, ERK1/2, RhoA

Received: January 01, 2015 Accepted: March 02, 2015 Published: March 29, 2015

Abstract

Our previous studies demonstrate that CXCL6/CXCR6 chemokine axis induces prostate cancer progression by the AKT/mTOR signaling pathway; however, its role and mechanisms underlying invasiveness and metastasis of breast cancer are yet to be elucidated. In this investigation, CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 shows a higher epithelial staining in breast cancer nest site and metastatic lymph node than the normal breast tissue, suggesting that CXCR6 may be involved in breast cancer (BC) development. In vitro and in vivo experiments indicate that overexpression of CXCR6 in BC cells has a marked effect on increasing cell migration, invasion and metastasis. In contrast, reduction of CXCR6 expression by shRNAs in these cells greatly reduce its invasion and metastasis ability. Mechanistic analyses show that CXCL16/CXCR6 chemokine axis is capable of modulating activation of RhoA through activating ERK1/2 signaling pathway, which then inhibits the activity of cofilin, thereby enhancing the stability of F-actin, responsible for invasiveness and metastasis of BC.

Taken together, our data shows for the first time that the CXCR6 / ERK1/2/ RhoA / cofilin /F-actin pathway plays a central role in the development of BC. Targeting the signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for BC.


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