You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology V1 Apr 2016MP88-11 THERAPEUTIC EFFECTS OF A MICRORNA-21 CHEMICAL INHIBITOR ON BLADDER CANCER PRECLINICAL MODELS ALEXANDRA DRAKAKI, NEIL O'BRIEN, CHRISTINA VORVIS, DIMITRIOS ILIOPOULOS, and DENNIS SLAMON ALEXANDRA DRAKAKIALEXANDRA DRAKAKI More articles by this author , NEIL O'BRIENNEIL O'BRIEN More articles by this author , CHRISTINA VORVISCHRISTINA VORVIS More articles by this author , DIMITRIOS ILIOPOULOSDIMITRIOS ILIOPOULOS More articles by this author , and DENNIS SLAMONDENNIS SLAMON More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2429AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES MicroRNAs are small non-coding RNAs that have been implicated in the pathogenesis of multiple types of cancer, including bladder cancer. Furthermore, microRNAs are central regulators of essential signaling pathways involved in cell proliferation and oncogenic pathways. Thus, targeting the expression levels of microRNAs could have therapeutic potential for cancer patients. MicroRNA-21 is highly up-regulated and has oncogenic function in most cancer types. We were interested in studying its role in bladder cancer and evaluate the therapeutic potential of its inhibition in vitro and in vivo METHODS MiR-21 expression levels were assessed by real-time PCR in a cohort of human bladder normal and cancer tissues and also in a bladder cancer cellular platform consisting of 28 bladder cancer cellular models. A chemically modified (locked nucleic acid) inhibitor of miR-21 (LNA-miR-21, Exiqon) was used to perform bladder cancer growth inhibition assays, using dose-escalating concentrations (1-50 uM). Two bladder cancer xenograft models were used to assess the LNA-miR-21 effectiveness to suppress bladder cancer tumor growth in vivo. Specifically, immunodeficient mice were injected in the right flank with 5367 or RT112 bladder cancer cells and when the tumors reached a size of ~300mm3, the mice were randomly assigned into 3 treatment groups; a vehicle control, a non-targeting control and LNA-miR-21 treatment group (n = 5). All the treatments were performed intravenously every 5 days for total of 3 treatments. Tumor xenografts were measured with calipers three times per week, and tumor volume in mm3 was determined by multiplying height x width x length RESULTS MiR-21 was found to be 5-fold up-regulated in bladder tumors relative to normal tissues and 3-fold in advanced (stage III,IV) relative to early stage bladder tumors, suggesting its potential involvement in bladder cancer progression. In addition, the 28 bladder cancer cellular models were stratified in 3 groups (high, intermediate, low expression) according to miR-21 expression levels. Bladder cancer cell line 5367 (high miR-21 expression) and the RT112 cell line (intermediate miR-21 expression), were chosen to evaluate LNA-miR-21 effects in vitro and in vivo. Response to LNA-miR-21 in vitro and in vivo was proportional to mir-21 levels. A 50uM dose of LNA-miR-21 suppressed 43.5% and 10% the growth of 5367 and RT112 cell lines, respectively. IV administration of the LNA-miR-21 (15mg/kg) induced inhibition of tumor progression in xenografts as measured on day 16 of treatment. A greater anti-tumor response was observed in the high expressing 5367 xenografts (greater than 100% tumor growth inhibition) relative to the RT112 xenografts (90% tumor growth inhibition). CONCLUSIONS Correlation between miR-21 expression levels and bladder tumor stage is suggestive of miR-21 potential involvement in bladder cancer progression. Chemical inhibition of this microRNA leads to growth inhibition both in vitro and in vivo. Most importantly increased levels of microRNA-21 expression correlate with the response to treatment making this microRNA not only a druggable target but a potential biomarker of response. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1133 Advertisement Copyright & Permissions© 2016MetricsAuthor Information ALEXANDRA DRAKAKI More articles by this author NEIL O'BRIEN More articles by this author CHRISTINA VORVIS More articles by this author DIMITRIOS ILIOPOULOS More articles by this author DENNIS SLAMON More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...