Abstract
Background: Increasing evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in cancer tumorigenesis and progression. TMPO antisense RNA 1 (TMPO-AS1) has been found to be involved in several cancers by acting as a competing endogenous RNA. However, the potential roles of TMPO-AS1 in bladder cancer (BC) and the potential interactions with proteins remain poorly understood.Methods: The expression of the lncRNA TMPO-AS1 was evaluated via bioinformatic analysis and further validated by quantitative real-time PCR (qRT-PCR). Loss- and gain-of-function assays were performed to determine the biological functions of TMPO-AS1 in BC cell proliferation, migration, and invasion. Moreover, chromatin immunoprecipitation, Western blotting, and fluorescence in situ hybridization, as well as RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays, were conducted to explore the upstream and downstream molecules interacting with TMPO-AS1.Results: TMPO-AS1 is upregulated in BC. Functional experiments demonstrated that TMPO-AS1 promotes cell proliferation, migration, and invasion in BC and inhibits cell apoptosis in vivo and in vitro. Mechanically, E2F1 is responsible for TMPO-AS1 upregulation. Additionally, TMPO-AS1 facilitates the interaction of E2F1 with OTU domain-containing ubiquitin aldehyde binding 1 (OTUB1), leading to E2F1 deubiquitination and stabilization; therefore, TMPO-AS1 promotes BC malignant phenotypes. Furthermore, rescue experiments showed that TMPO-AS1 promotes BC growth in an E2F1-dependent manner.Conclusions: Our study is the first to uncover the novel TMPO-AS1/E2F1 positive regulatory loop important for the promotion of BC malignant behaviors. The TMPO-AS1/E2F1 loop should be considered in the quest for new BC therapeutic options.
Highlights
Bladder cancer (BC) is the most common malignant tumor of the urinary system worldwide [1]; about 549,393 new cases and 199,922 cancer-related deaths were reported in 2018 [2]
We demonstrate that E2F1 activates the transcription of TMPO-AS1, which, in turn, facilitates the interaction of E2F1 with OTU domain-containing ubiquitin aldehyde binding 1 (OTUB1), a deubiquitinase; the E2F1 protein levels are increased via stabilization, promoting BC malignant phenotypes
The expression of TMPO-AS1 was upregulated in BC tissues compared with the normal tissues according to The Cancer Genome Atlas (TCGA) (Figure 1B) and TANRIC databases (Figure 1C)
Summary
Bladder cancer (BC) is the most common malignant tumor of the urinary system worldwide [1]; about 549,393 new cases and 199,922 cancer-related deaths were reported in 2018 [2]. The majority of BC cases are urothelial cell carcinomas. Urothelial BC can be categorized into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). 75% of patients with BC exhibit NMIBC with high recurrence and progression, while the remaining 25% of patients with BC present with MIBC and have a poor prognosis [3]. Increasing evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in cancer tumorigenesis and progression. The potential roles of TMPO-AS1 in bladder cancer (BC) and the potential interactions with proteins remain poorly understood
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