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Tumor Suppressor Functions of miRNA-375 in Nasopharyngeal Carcinoma through Inhibition of Ubiquitin-Specific Protease 1 Expression


 Background: Nasopharyngeal carcinoma (NPC) development involves many genetic alterations. This study profiled differentially expressed miRNAs and selected miR-375 for further study.Methods: Differentially expressed miRNAs (DE-miRNAs) were screened using online databases and subjected to various analyses. miR-375 mimics with negative control cDNA, and ubiquitin-specific protease 1 (USP1) as well as a vector-only control were transfected into NPC cells for analysis by quantitative PCR, western blotting, wound healing, Transwell, cell viability, flow cytometry, and luciferase gene reporter assays.Results: A total of 308 NPC and 23 normal tissues were analyzed, and 67 DE-miRNAs were identified. Among these, miR-375 was downregulated and miR-21-5p was upregulated. Bioinformatical analysis identified USP1 as a potential target gene of miR-375. Furthermore, miR-375 expression was decreased, whereas USP1 expression was increased in NPC. Increased USP1 expression was associated with poor survival of head and neck cancer patients. The luciferase assay confirmed miR-375 binding to the USP1 3'-untranslated region (UTR), while the transfection experiment confirmed miR-375 expression reduced USP1 expression, and USP1 overexpression reversed the anti-tumor activity of miR-375 in NPC cells, determined by tumor cell migration, invasion, apoptosis, and gene expression. In addition, USP1 overexpression activated phosphoinositide 3-kinase (PI3K) signaling, whereas a selective PI3K inhibitor (S2793) could reverse the effects of USP1 on NPC cells in vitro.Conclusions: This study confirmed decreased miR-375 expression and increased miR-21 expression in NPC tissues. Downregulated miR-375 expression led to USP1 upregulation, which in turn activated PI3K/Akt signaling and promoted NPC cell migration and invasion, but inhibited NPC cell apoptosis.