Abstract
BackgroundThe benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. New treatments demand prompt exploration for clinical therapies. Ubiquitin-specific peptidase 39 (USP39) serves as the pro-tumor factor in several previous studies of other malignant tumors. To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC.MethodsWe applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. USP39 knockdown or overexpression plasmids were transfected into 786-O and ACHN cells. The HUVEC received cell supernatants of 786-O and ACHN cells with knockdown or overexpression USP39.The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by affinity purification and mass spectrometry, co-immunoprecipitation and Western blot assays.ResultsThe mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P < 0.001), and negatively correlated with the survival rate of RCC patients (P < 0.01). Silencing of USP39 in 786-O and ACHN cells inhibited cell proliferation and colony formation, and induced S phase arrest. USP39 overexpression significantly increased the number of tubules (P < 0.05) and branches (P < 0.01) formed by HUVEC cells, and USP39 knockdown produced an opposite effect (P < 0.05). The USP39 (101–565) fragment directly mediated its binding to SRSF1 and SRPK1, and promoted the phosphorylation of SRSF1 to regulate VEGF-A alternative splicing. USP39 knockdown upregulated the expression of VEGF-A165b, and USP39 overexpression downregulated the expression of VEGF-A165b significantly (both P < 0.05).ConclusionUSP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through inhibiting VEGF-A165b alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC.Graphic abstract
Highlights
Renal cell carcinoma (RCC) is one of the most lethal malignancies of the genitourinary system causing approximately 140,000 deaths each year worldwide [1, 2]
Ubiquitin-specific peptidase 39 (USP39) acted as a pro-tumor factor by motivating the malignant biological processes of renal cell carcinoma (RCC), probably through inhibiting vascular endothelial growth factor (VEGF)-A165b alternative splicing and regulating Serine/Arginine-Rich Splicing Factor 1 (SRSF1) and SRPK1
The aim of the present study was to investigate the role of USP39 in RCC cell proliferation, malignant progression and angiogenesis and the potential mechanism of VEGF-A alternative splicing, in an attempt to gain deeper insights into the molecular mechanism underlying the development of RCC and provide new clues for exploring molecular targeted therapies of RCC
Summary
Renal cell carcinoma (RCC) is one of the most lethal malignancies of the genitourinary system causing approximately 140,000 deaths each year worldwide [1, 2]. 20–40% RCC patients may experience recurrence or metastasis one or two years after the initial surgery with poor survival and prognosis [5]. The advent of targeted therapy including tyrosine kinase inhibitors (TKIs) has improved overall survival (OS) and progression-free survival (PFS) of patients with advanced RCC, drug resistance and rapid disease progression occurred frequently [7]. The benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. To investigate the function and mechanism of USP39 in promot‐ ing malignant proliferation and angiogenesis of RCC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
