LncRNA PVT1 promotes bladder cancer progression by forming a positive feedback loop with STAT5B

Abstract

BackgroundPlasmacytoma Variant Translocation 1 (LncRNA PVT1) and signal transducer and activator of transcription 5B (STAT5B) play important roles in various cancers, but their interaction in bladder cancer (BC) remains unclear. PurposeWe aimed to explore the interaction between lncRNA PVT1 and STAT5B in BC tumorigenesis and find potential drugs for BC. MethodsThe association of the expression of lncRNA PVT1 and STAT5B to the prognosis of BC patients was evaluated via bioinformatic analysis. Loss- and gain-of-function assays were performed to determine the biological functions of lncRNA PVT1 and STAT5B. Quantitative real time polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence were used to detect lncRNA PVT1 and STAT5B expression. Fluorescence in situ hybridization, RNA pull-down and RNA immunoprecipitation assays were conducted to determine the regulatory effect of lncRNA PVT1 on STAT5B. The transcriptional effect of STAT5B on lncRNA PVT1 gene was determined using luciferase reporter assay, chromatin immunoprecipitation and DNA-affinity precipitation assays. Connectivity Map analysis was used to screen anticancer drugs. ResultsLncRNA PVT1 and STAT5B enhance the expression of each other and promote the malignant phenotypes in BC, including cell viability and invasion. lncRNA PVT1 stabilizes STAT5B by decreasing ubiquitination, enhances STAT5B phosphorylation, and promotes the translocation to the nucleus of STAT5B to trigger further carcinogenesis activities. In the nucleus, STAT5B activates the transcription of lncRNA PVT1 by binding directly to its promoter region, leading to a positive feedback. Tanespimycin effectively abated the oncogenic effect. ConclusionsWe first identified the lncRNA PVT1/STAT5B positive feedback loop for bladder carcinogenesis, and found a potentially effective drug for BC.