Abstract OBJECTIVE: Wilms' tumor (WT) is the most common malignant renal tumor in children. MicroRNAs (MiRNAs) function in the progression of various cancers. Recent reports have reported that miR-140-5p and miR-92a-3p are dysregulated in WT tissues, but the potential mechanisms of the two miRNAs in modulating WT progression are still poorly understood. MATERIALS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRTPCR) was conducted to detect the expression levels of miR-140-5p, miR-92a-3p, and fibroblast growth factor receptor substrate 2 (FRS2) in WT tissues and cells, as well as matched controls. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometry assay were employed to check cell proliferation and apoptosis, respectively. The abilities of cell migration and invasion were evaluated by transwell assay. The protein level of FRS2 in samples was measured by Western blot. The starBase was used to predict the binding sites between FRS2 and miR-140-5p or miR-92a-3p and the Dual-Luciferase reporter assay was performed to verify the interaction. Xenograft tumor model was established to investigate the biological roles of the two miRNAs in WT in vivo. RESULTS: The levels of miR-140-5p and miR-92a-3p were significantly downregulated in WT tissues and cells, while the expression of FRS2 was significantly upregulated. The two miRNAs both inhibited proliferation, migration, invasion, and induced apoptosis of WT cells. Besides, FRS2 was a target of the two miRNAs and its overexpression reversed the effects of the two miRNAs-mediated suppression on WT progression. Moreover, the upregulation of the two miRNAs repressed tumor growth in vivo. CONCLUSIONS: MiR-140-5p and miR-92a-3p attenuated the aggressive progression of WT via targeting FRS2.