CCR7 mediates the TNF-α-induced lymphatic metastasis of gallbladder cancer through the -ERK1-2 - AP-1- and -JNK - AP-1- pathwaysReport as inadecuate

CCR7 mediates the TNF-α-induced lymphatic metastasis of gallbladder cancer through the -ERK1-2 - AP-1- and -JNK - AP-1- pathways - Download this document for free, or read online. Document in PDF available to download.

Journal of Experimental and Clinical Cancer Research

, 35:51

First Online: 24 March 2016Received: 02 November 2015Accepted: 02 March 2016DOI: 10.1186-s13046-016-0318-y

Cite this article as: Hong, H., He, C., Zhu, S. et al. J Exp Clin Cancer Res 2016 35: 51. doi:10.1186-s13046-016-0318-y


BackgroundCC-chemokine receptor 7 CCR7, which plays an important role in cell directional movement, is highly expressed in various cancers and positively related to lymph node metastasis. The inflammatory cytokine tumour necrosis factor TNF-α promotes tumour progression and lymph node metastasis in gallbladder cancer GBC. However, the expression of CCR7 in GBC is unclear, and its role in the TNF-α-induced lymphatic metastasis of GBC requires further research.

MethodsThe expression of CCR7 in clinical samples was detected by immunohistochemistry, and the relationship between CCR7 and clinicopathological factors or the TNF-α level of the bile was analyzed. After treatment with various concentrations of TNF-α, CCR7 expression in GBC cell lines was measured by Western blotting. The relative luciferase reporter assay, site-directed mutagenesis and chromatin immunoprecipitation were used to analyze the promoter activity and transcriptional regulation of CCR7. MAPKs inhibitors were used to explore the upstream signalling molecules of AP-1. We established a NOZ cell line stably expressing lentiviral CCR7 shRNA that effectively silenced the expression of CCR7, and to determine the role of TNF-α - CCR7 axis in the migration of GBC cells to the lymphatic system by transwell assays and animal experiments.

ResultsCCR7 was highly expressed in GBC samples. Higher expression of CCR7 was associated with American Joint Committee on Cancer AJCC staging and lymph node metastasis. Moreover, we found that CCR7 expression in GBC tissue was positively correlated with the levels of TNF-α in the bile, and that TNF-α enhanced the promoter activity and protein expression of CCR7 through the -ERK1-2-AP-1- and -JNK-AP-1- pathways. Finally, we revealed that TNF-α could promote GBC cell migration to lymphatic endothelial cells or lymph nodes through upregulation of CCR7 in vitro and in vivo.

ConclusionsOur study suggests that CCR7 is highly expressed in GBC, and mediates the TNF-α-induced lymphatic metastasis of GBC through the -TNF-α - ERK1-2 - AP-1 - CCR7- and -TNF-α - JNK - AP-1 - CCR7- pathways.

KeywordGallbladder cancer CCR7 TNF-α Cancer-related inflammation Lymphatic metastasis AbbreviationsAP-1activator protein-1

CCR7CC-chemokine receptor 7

GBCgallbladder cancer

HDLECshuman dermal lymphatic endothelial cells

LNMlymph node metastasis

TNF-αtumour necrosis factor-alpha

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Author: HaiJie Hong - CaiLong He - SiYuan Zhu - YanHui Zhang - XiaoQian Wang - FeiFei She - YanLing Chen


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