AbstractBackgroundLiposarcoma (LPS) is one of the most common soft tissue malignancies in adults, and it is characterized by dysregulation of multiple signaling pathways, including MDM2 proto‐oncogene (MDM2) amplification. MicroRNA (miRNA) regulates gene expression through incomplete complementary pairing with the 3' untranslated region of mRNAs involved in tumor progression.MethodsIn this study, bioinformatics analysis, RT‐qPCR, dual‐luciferase reporter gene, MTT, flow cytometry, cell scratches, chamber migration, colony formation, FISH, WB, and CCK8 were used.ResultsRT‐qPCR showed that the expression of MDM2 was increased when miR‐215‐5p was overexpressed compared with the control group. The dual‐luciferase reporter gene showed that the Renilla ratio firefly fluorescence intensity was decreased in the overexpression group compared with the control group. Cell phenotype experiments revealed that the overexpression group had increased cell proliferation rate, increased apoptosis rate, increased colony formation rate, increased cell healing area ratio, and increased number of cell invasions. FISH revealed increased MDM2 expression in the overexpression group. WB suggested decreased Bax expression, increased PCNA, Bcl‐2, and MDM2 expression, and decreased P53 and P21 expression in the overexpression group.ConclusionsIn this study, we suggest that miR‐215‐5p can target and promote MDM2 expression, promote the proliferation and invasion of LPS cells SW‐872, and inhibit apoptosis.Targeting miR‐215‐5p may be a novel therapeutic strategy for the treatment of LPS.