Abstract
Nasopharyngeal carcinoma (NPC) development involves many genetic alterations. This study profiled differentially expressed microRNAs (DE-miRNAs) and selected miR-375 for further study. DE-miRNAs were screened using online databases and subjected to various analyzes. miR-375 mimics with negative control (NC) cDNA, and a ubiquitin-specific protease 1 (USP1) as well as a NC group were transfected into NPC cells for analysis by quantitative PCR, western blotting, wound healing, Transwell, flow cytometry, cell counting kit-8 (CCK-8), and luciferase gene reporter assays. Among these DE-miRNAs, miR-375 was downregulated and miR-21 was upregulated in NPC cells. Bioinformatical analysis identified USP1 as a potential target gene of miR-375. 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. USP1 overexpression reversed the anti-tumor activity of miR-375 in NPC cells as determined by tumor cell migration, invasion, apoptosis, and viability assays. In addition, USP1 overexpression activated phosphoinositide 3-kinase (PI3K) signaling, whereas a selective PI3K inhibitor (S2739) could reverse the effects of USP1 on NPC cells in vitro. miR-375 and miR-21 are both related to NPC and miR-375 can target USP1. Further experiments revealed that up-regulated miR-375 expression led to USP1 down-regulation, and miR-375 overexpression suppressed PI3K/Akt signaling and inhibited NPC cell migration and invasion, but promoted NPC cell apoptosis.
Highlights
Nasopharyngeal carcinoma (NPC), the most common cancer originating in the nasopharynx, differs significantly from other head and neck cancers in terms of risk factors, pathogenesis, clinicopathological characteristics, and treatment options [1]
MiR-375 expression was decreased, whereas ubiquitin-specific protease 1 (USP1) expression was increased in NPC
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
Summary
Nasopharyngeal carcinoma (NPC), the most common cancer originating in the nasopharynx, differs significantly from other head and neck cancers in terms of risk factors, pathogenesis, clinicopathological characteristics, and treatment options [1]. The majority of NPC patients are geographically localized to Southeast Asia, while China has the highest incidence and mortality rates[3; 4]. Activation of nuclear factor-kappa B (NF-κB) signaling has been shown in approximately 50% of NPC cases [6; 7]. NPC patients can be treated with surgery, chemotherapy, radiotherapy, and immune-based therapy[8]. The development of more effective treatments for NPC is urgently needed. Nasopharyngeal carcinoma (NPC) development involves many genetic alterations. This study profiled differentially expressed miRNAs and selected miR-375 for further study
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