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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.
Highlights
Chemokines are a family of small (8–14 kDa), mostly basic, heparin-binding cytokines that primarily induce directed migration of various types of leukocytes through interactions with a group of seven transmembrane G protein-coupled receptors (GPCR) [1]
These findings suggest that the stress fibers formation by CXCL16/CXCR6 chemokine axis is potentially responsible for RhoA/cofilin pathway, which is capable of enhancing stability of stress fibers
Increasing evidence has shown that CXCL16/CXCR6 chemokine axis plays multifaceted roles in a variety of cancers, including three major aspects of their activities: (1) CXCL16/CXCR6 functions as a regulator in migration and proliferation of a variety of cancer cells [3, 33,34,35]; (2) CXCR6 functions as a newly defined biomarker of tissue-specific stem cell [16]; (3) regulating angiogenic processes [15]
Summary
Chemokines are a family of small (8–14 kDa), mostly basic, heparin-binding cytokines that primarily induce directed migration of various types of leukocytes through interactions with a group of seven transmembrane G protein-coupled receptors (GPCR) [1]. Over 50 chemokines and 20 chemokine receptors have been identified, and are grouped into four categories (C, CC, CXC and CX3C) according to the location of the main cysteine residues near the N terminal of these proteins [1]. The chemokine receptor system extends to most human neoplastic cells and was found to be altered dramatically in neoplastic tissue, at the leading edge of invasion [2]. CXCR6 was identified as a cognate receptor of CXCL16 usually expressed by peripheral blood leukocytes [7]. CXCR6 has been shown to be present in prostate tissues and in the marrow [8]
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