College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Dongguk-ro 32, Ilsandong-gu, Goyang, Gyeonggi 10326, Korea.
Int J Mol Sci. 2020 Dec 23;22(1):89. doi: 10.3390/ijms22010089.
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 β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) 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-1α 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-1α 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-1α/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.
趋化因子-受体相互作用在癌症进展中发挥多种作用。据报道，趋化因子 X-C 基序趋化因子受体 1（XCR1）的过表达，即趋化因子 X-C 基序趋化因子配体 1（XCL1）的特异性受体，可刺激 MDA-MB-231 三阴性乳腺癌细胞的迁移。然而，这一过程的确切机制仍有待阐明。我们的研究发现，XCL1 处理显著增强了 MDA-MB-231 细胞的迁移。此外，XCL1 通过下调 E-钙黏蛋白和上调 N-钙黏蛋白和波形蛋白以及增加 β-连环蛋白核易位，增强 MDA-MB-231 细胞的上皮-间充质转化（EMT）。此外，XCL1 增强了缺氧诱导因子-1α（HIF-1α）的表达和细胞外信号调节激酶（ERK）1/2 的磷酸化。值得注意的是，使用 siRNA 敲低 XCR1 可否定 XCL1 对细胞迁移和细胞内信号的影响，证实了 XCR1 介导的作用。用 U0126（一种特定的丝裂原活化蛋白激酶激酶（MEK）1/2 抑制剂）处理 MDA-MB-231 细胞，阻断了 XCL1 诱导的 HIF-1α 积累和细胞迁移。还在 ER/HER2 SK-BR-3 细胞中评估了 XCL1 对细胞迁移的影响。XCL1 也促进了 SK-BR-3 细胞的细胞迁移、EMT 诱导、HIF-1α 积累和 ERK 磷酸化。虽然 XCL1 对 MDA-MB-231 细胞中基质金属蛋白酶（MMP）-2 和 MMP-9 的表达没有显著影响，但它增加了 SK-BR-3 细胞中这些酶的表达。总之，我们的结果表明，ERK/HIF-1α/EMT 通路的激活参与了 XCL1 诱导的 MDA-MB-231 和 SK-BR-3 乳腺癌细胞的迁移。基于我们的发现，XCL1-XCR1 相互作用及其相关信号分子可能成为预防乳腺癌细胞迁移和转移的特定靶点。
