Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells

Abstract

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.

C chemokines are prognostic biomarkers correlated with diverse immune cell infiltrations in clear cell renal cell carcinoma

“…In lung cancer, XCL1 promoted the proliferation and migration of cancer cells through the JAK2/STAT3 signaling pathway (37). Additionally, in breast cancer, XCL1 stimulated metastasis via enhancing epithelial-mesenchymal transition (EMT) (38). Moreover, XCL1 is a potential biomarker that can be used to predict the malignant transformation of mature cystic teratoma into squamous cell carcinoma (39).…”

“…They are important regulators of various biological processes, such as innate and adaptive immunity and inflammation, and play a crucial role in the development of cancers (7,10). Accumulating evidence has confirmed the pro-metastatic effect of the XCL1/XCR1 axis (36)(37)(38). Moreover, many studies have focused on applying small-molecule modulators targeting TLRs for cancer treatment (42,43).…”

Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress

“…The human BC cell lines including MDA-MB-231 and MCF-7 cells were supplied by the American Type Culture Collection (Manassas, VA, USA). These cells were maintained in DMEM containing 10% FBS and 1% antibiotic–antimycotic (final concentrations of 100 U/mL penicillin and 100 µg/mL streptomycin) in a humidified incubator at 37 °C with 5% CO 2 , as previously described [ 24 , 25 ].…”

“…MDA-MB-231 and MCF-7 cells were seeded in 60-mm culture dishes at a density of 1 × 10 6 cells/well and 1.2 × 10 6 cells/well, respectively, and incubated at 37 °C overnight to 75–80% confluence. Then, siRNA control and siRNA LC3B were transfected to MDA-MB-231 and MCF-7 cells using Lipofectamine 2000 transfection reagent (Invitrogen, Rockford, IL, USA) following the manufacturer’s instructions and as previously reported [ 24 ]. After 6 h of transfection, media containing siRNAs were replaced with new culture media, and cells were plated for further experiments including western blotting, SRB assay, and visualization of cell morphology.…”

BHLHE41 Overexpression Alleviates the Malignant Behavior of Colon Cancer Cells Induced by Hypoxia via Modulating HIF-1α/EMT Pathway

“…Hypoxia of tumor tissue has been corroborated to be an important reason in leading the tumor malignant development, drug resistance, and the metastasis of recurrent lesions [ 11 ]. In the hypoxic microenvironment, tumor cells highly express hypoxia-inducible factor-1 (HIF-1 α ), which promotes the tumor cell heterogeneity and tumor angiogenesis, as well as tumor cell infiltration and metastasis [ 12 ]. Epithelial-mesenchymal transition (EMT) is involved in the initiation process of tumor malignant phenotype transformation and is a key step in tumor metastasis [ 13 ].…”