MicroRNA-4500 Inhibits Migration, Invasion and Angiogenesis of Breast Cancer Cells via RRM2-dependent MAPK Signaling Pathway

Abstract Considering the dynamic role of microRNAs (miRNAs) in breast cancer, miRNAs may serve as therapeutic targets, helping to prevent development of therapy resistance, maintain stable disease, and prohibit metastatic spread. We identified the differentially expressed breast cancer-related gene RRM2 as the study focus through microarray expression profiles. Next, the upstream regulatory miR-4500 of RRM2 was predicted using bioinformatics website analysis, and their binding was verified by dual luciferase reporter gene assay. The regulatory effects of miR-4500 on breast cancer cell proliferation, apoptosis, migration, invasion and capillary-like tube formation of endothelial cells were assessed by gain- and loss-of-function experiments. The experimental data revealed miR-4500 was down-regulated while RRM2 was up-regulated in breast cancer cells. Mechanistic analysis revealed that miR-4500 down-regulated the RRM2 expression to inactivate the MAPK signaling pathway. Furthermore, miR-4500 exerted anti-tumor effects by targeting RRM2 through suppression of the MAPK signaling pathway in vitro, evidenced by attenuated cancer cell migration, invasion and capillary-like tube formation of endothelial cells. The in vivo experiments further corroborated in vitro results. Collectively, over-expressed miR-4500 could down-regulate RRM2 and inhibit activation of the MAPK signaling pathway, thus attenuating breast cancer cell proliferation, invasion, migration, angiogenesis and promoting breast cancer cell apoptosis.