期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 1, 页码 -出版社
MDPI
DOI: 10.3390/ijms22010089
关键词
chemokine; XCL1; XCR1; breast cancer cells; MDA-MB-231 cells; SK-BR-3 cells; cell migration; ERK; HIF-1 alpha; EMT
资金
- Korean government (MSIT) [NRF-2018R1A5A2023127]
The study revealed that XCL1 enhances cell migration and epithelial-mesenchymal transition in breast cancer cells MDA-MB-231 and SK-BR-3 through the activation of ERK/HIF-1α/EMT signaling pathway. The XCL1-XCR1 interaction may serve as a specific target for preventing breast cancer cell migration and metastasis.
Chemokine-receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial-mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in beta-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1 alpha accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2(+) SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1 alpha accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1 alpha/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1-XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.
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