Abstract
BackgroundNPL4 is an important cofactor of the valosin-containing protein (VCP)–NPL4–UFD1 complex. The VCP–NPL4–UFD1 has been considered as a ubiquitin proteasome system (UPS) regulator and response to protein degradation. While NPL4 plays important roles in various diseases, little is known about its functions in bladder cancer (BC).MethodsMTT assays and colony forming test were performed to evaluate cell proliferation ability and Western blotting was used to detect protein expression. Cyclin D1 mRNA expression was detected using qRT-PCR, and coimmunoprecipitation (CoIP) was used to detect protein–protein interactions.ResultsNPL4 was upregulated in BC tissue and correlated with poor prognosis. Upregulation of NPL4 promoted cell proliferation while suppression of NPL4 reduced BC cell proliferation. Upregulation of NPL4 led to overexpression of cyclin D1 by enhancing its mRNA stability. Moreover, NPL4 was found to bind directly to DXO and induce its degradation. DXO was downregulated in BC tissue and regulated BC cell proliferation by destabilizing cyclin D1 mRNA. DXO-mediated NPL4 regulated BC cell proliferation by stabilizing cyclin D1 expression.ConclusionsThe NPL4/DXO/cyclin D1 axis exert crucial role in BC cell growth and is associated with prognosis and may represent a potential therapeutic target for BC.
Highlights
Nuclear protein localization protein 4 homolog (NPL4) is an important cofactor of the valosin-containing protein (VCP)–NPL4–ubiquitin fusion degradation-1 (UFD1) complex
NPL4 is upregulated in bladder cancer (BC) tissues and is associated with poor prognosis To identify whether NPL4 level were changed in BC tissue, quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was used to validate NPL4 mRNA expression in BC and normal bladder tissues
The results was confirmed by the microarray data from the TCGA database, and found that NPL4 mRNA expression was increased in BC tissue (Fig. 1b)
Summary
NPL4 is an important cofactor of the valosin-containing protein (VCP)–NPL4–UFD1 complex. While NPL4 plays important roles in various diseases, little is known about its functions in bladder cancer (BC). Bladder cancer (BC) is the fourth commonly diagnosed cancer in men and the 11th most frequently diagnosed cancer in women [1]. 79,030 new BC patients and 16,870 cancer-related deaths were reported in the United States [2]. 70% of all BC cases are NMIBC [4] and around 50% of NMIBC patients exhibit recurrence after transurethral resection [5]. Many patients progress to muscle-invasive disease due to multiple recurrences [6]. Understanding the molecular mechanism of bladder tumorigenesis and discovering new treatment strategies are urgently required to improve diagnosis and treatment of BC [7, 8]
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