The Chemokine Receptor CXCR4 and c-MET Cooperatively Promote Epithelial-Mesenchymal Transition in Gastric Cancer Cells

Abstract

The C-X-C motif chemokine receptor 4 (CXCR4) pathway can promote tumor metastasis but is dependent on cross talk with other signaling pathways. The MET proto-oncogene (c-MET) participates in metastasis and is highly expressed in gastric cancer. However, the relationship between CXCR4 and c-MET signaling and their mechanisms of action in gastric cancer metastasis remain unclear. In this study, in vitro experiments demonstrated that C-X-C motif chemokine ligand 12 (CXCL12)/CXCR4 induces epithelial-mesenchymal transition (EMT) and promotes migration in gastric cancer cells, which is accompanied by c-MET activation. These phenomena were reversed by c-MET inhibition. Further investigation revealed that c-MET activation correlated with its interaction with caveolin 1 in lipid rafts, induced by CXCL12. In clinical samples, we observed a significant positive association between CXCR4 expression and c-MET phosphorylation (r = 0.259, P = .005). Moreover, samples expressing both receptors were found to indicate significantly poorer patient prognosis (P < .001). These results suggest that CXCL12 induces EMT at least partially through cross talk between CXCR4 and c-MET signaling. In addition, changes in these pathways could have clinical importance for the treatment of gastric cancer.

miR-204-5p Suppress Lymph Node Metastasis via Regulating CXCL12 and CXCR4 in Gastric Cancer

“…To further elucidate the target mRNAs of miR-204-5p regulation that contributed to the suppressive role of GC metastasis, complementary sequence of miR-204-5p is identified in the 3'-UTR of Chemokine ligand 12 (CXCL12)/chemokine receptor 4 (CXCR4) mRNA by Targetscan. Previous studies have shown the CXCL12/CXCR4 axis is positively associated with the aggressive phenotypes of GC [27][28][29][30]. Further study revealed that CXCL12 and CXCR4 protein expression is increased in GC tissue with lymph nodes (LN) metastatic and mainly expressed in metastatic lymph nodes [31,32].…”

Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

“…Radioprotection by CXCL12 might also be relevant in various cancers, in addition to the established role of CXCL12 in supporting epithelial-to-mesenchymal transition that results in cancer metastasis. 17,25,27,28,81,[96][97][98] Using the inducible mouse model to test this will provide a better understanding of the consequence of elevated CXCL12 in a disease state and enable physicians to create better treatment plans.…”

Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

“…Thus, the elevation of CXCL12 upon stress might be a self-preservation mechanism that cells adopt in emergency conditions. Radioprotection by CXCL12 might also be relevant in various cancers, in addition to the established role of CXCL12 in supporting epithelial-to-mesenchymal transition that results in cancer metastasis (Cheng et al, 2018;Cordeiro Gomes et al, 2016;Domanska et al, 2013;Meng et al, 2018;Ratajczak et al, 2006;Shan et al, 2015;Tang et al, 2019;Teicher and Fricker, 2010;Yu et al, 2017;Zhou et al, 2019). Using the inducible mouse model to test this will provide a better understanding of the consequence of elevated CXCL12 in a disease state and enable physicians to create better treatment plans.…”