The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.
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We acknowledge the use of NCBI GEO database, such as GSE29272, GSE15459 and GSE62254. This study was supported by the National Natural Science Foundation of China (No. 81272643 and No. 81272637) and ‘3 & 3’ project of The First Affiliated Hospital of Sun Yat-sen University.
CHZ, ZX, GGX and ZWW designed the study. ZX, ZJZ, ZWW, XHZ, GKX and JTZ performed the study. ZX, CHZ, WC, RES, RAB, NA and YLH analyzed the data and wrote the paper.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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Xiang, Z., Zhou, Z., Xia, G. et al. A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis. Oncogene 36, 5122–5133 (2017) doi:10.1038/onc.2017.108
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