TNF-α promotes TNBC aggressiveness by upregulating miR-5001-5p and inhibiting MNK2a–p38 MAPK signaling

Triple-negative breast cancer (TNBC) has a greater invasive and metastatic potential than non-TNBC, leading to a poorer prognosis because of the absence of viable therapeutic targets. Tumor necrosis factor-alpha (TNF-α), which is aberrantly activated in TNBC, plays a pivotal role in TNBC metastasis and progression. The ability of TNF-α to promote TNBC progression is unique when compared with its ability to promote non-TNBC progression; however, the underlying mechanism remains unclear. TNF-α specifically enhanced the invasive and metastatic potential of TNBC compared with that of non-TNBC. Analysis of the differentially expressed miRNAs showed that TNF-α upregulated miR-5001-5p expression in TNBC cells. The results of transcriptomic sequencing combined with subsequent verification analysis indicated that MNK2a was significantly downregulated following miR-5001-5p overexpression. Evidence from dual-luciferase reporter assays confirmed that miR-5001-5p bound to the MNK2a 3' UTR region and inhibited the activation of the p38 MAPK pathway. Our results provide novel insights into the molecular mechanism by which TNF-α promotes epithelial–mesenchymal transition in TNBC through the TNF-α–miR-5001-5p–MNK2a–p38 MAPK signaling axis, eventually enhancing the invasive and metastatic potential of TNBC. We discovered a novel mechanism of invasion and metastasis in TNBC whereby TNF-α upregulated the expression of miR-5001-5p, which downregulated MNK2a by binding to its 3' UTR region. This inhibited the activation of the p38 MAPK pathway, following which MNK2a promoted epithelial–mesenchymal transition in TNBC. This mechanism offers a theoretical basis for TNBC-targeted therapy and also serves as a novel therapeutic target.