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Characterization and therapeutic targeting of the miR-21/PPP2R2A/ERK molecular circuit in bladder cancer

ABSTRACT: MicroRNAs play an important role in the pathogenesis of different types of cancer including bladder cancer. MiR-21 has been identified to have an oncogenic function, while its inhibition suppresses tumor growth. Here, we followed an integrated bioinformatics and molecular analyses to identify the molecular mediators of miR-21 oncogenic function in bladder cancer and evaluate the therapeutic potential of a chemically-modified miR-21 inhibitor in bladder xenografts. MiR-21 expression was found to up-regulated in human bladder cancers relative to normal tissues and miR-21 inhibition suppressed bladder cancer cell properties, including growth, invasiveness and anchorage-independence. Intravenous administration of an antisense oligonucleotide against miR-21 harboring locked-nucleic-acid (LNA-miR-21) modifications blocked bladder tumor growth in vivo. Transcriptomic analysis of 28 bladder cancer cell lines revealed a gene signature that negatively correlated with miR-21 expression levels. Bioinformatics and 3’UTR luciferase assay analyses revealed a direct interaction between miR-21 the 3’UTR of PPP2R2A gene. Inhibition of PPP2R2A expression induced bladder cancer growth, suggesting its tumor suppressor function. Gene profiling followed by IPA network analysis revealed that PPP2R2A regulates the ERK1/2 molecular network. Taken together, PPP2R2A is the functional mediator of miR-21 oncogenic activity on bladder cancer and LNA-miR-21 could have a therapeutic potential in bladder cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97782 | GEO | 2018/04/19

REPOSITORIES: GEO

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2016-08-03 | E-GEOD-85116 | biostudies-arrayexpress

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2016-08-03 | GSE85116 | GEO

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Circular RNA circRIMS1 acts as a sponge of miR-433-3p to promote bladder cancer progression by regulating CCAR1 expression (mRNA)

Project description:Background: Circular RNAs (circRNAs), a subclass of noncoding RNAs, have been reported to be involved in the progression of various diseases. However, the exact role of circRIMS1, also termed hsa_circ_0132246, in human bladder cancer remains to be discovered. Methods: By performing RNA-seq comparing bladder cell lines and normal uroepithelial cells, circRIMS1 was selected as the research object. We further verified by qRT-PCR that circRIMS1 was upregulated in bladder cancer tissue and cell lines. Proliferation, colony formation, Transwell migration, Matrigel invasion, apoptosis, western blotting and in vivo tumorigenesis and metastasis assays were utilized to evaluate the roles of circRIMS1, miR-433-3p and CCAR1. For mechanistic investigation, RNA pull-down, fluorescence in situ hybridization (FISH) and luciferase reporter assay confirmed the binding of circRIMS1 with miR-433-3p. Results: CircRIMS1 was significantly upregulated in bladder cancer and circRIMS1 expression was associated with the pathological stage and histological grade of bladder cancer. Inhibition of circRIMS1 suppressed the proliferation, migration and invasion of bladder cancer cells in vitro and in vivo, while overexpression of circRIMS1 exerted the opposite effects. Moreover, the circRIMS1/miR-433-3p/CCAR1 regulatory axis was confirmed to be responsible for the biological functions of circRIMS1. Conclusions: CircRIMS1 acts as a tumor promoter in bladder cancer to enhance tumor growth, migration and invasion via the miR-433-3p/CCAR1 regulatory axis, which provides a new therapeutic target and a novel biomarker in bladder cancer. Keywords: CircRIMS1, Bladder cancer, miR-433-3p, CCAR1, Progression, Metastasis

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