MP17-03 MICRORNA LET-7F-5P IS A NOVEL BIOMARKER OF RECURRENCE AND A POTENTIAL THERAPEUTIC OPPORTUNITY IN NON-MUSCLE INVASIVE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (MP17)1 Apr 2020MP17-03 MICRORNA LET-7F-5P IS A NOVEL BIOMARKER OF RECURRENCE AND A POTENTIAL THERAPEUTIC OPPORTUNITY IN NON-MUSCLE INVASIVE BLADDER CANCER Kevin Shee*, Carmen J Marsit, Alan R Schned, Jason Pettus, David A Armstrong, Margaret R Karagas, Todd W Miller, John D Seigne, and Angeline S Andrew Kevin Shee*Kevin Shee* More articles by this author , Carmen J MarsitCarmen J Marsit More articles by this author , Alan R SchnedAlan R Schned More articles by this author , Jason PettusJason Pettus More articles by this author , David A ArmstrongDavid A Armstrong More articles by this author , Margaret R KaragasMargaret R Karagas More articles by this author , Todd W MillerTodd W Miller More articles by this author , John D SeigneJohn D Seigne More articles by this author , and Angeline S AndrewAngeline S Andrew More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000842.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: 50% to 75% of patients with non-muscle invasive bladder cancer (NMIBC) experience recurrences within 6 to 12 years of diagnosis, and the cost of screening makes bladder cancer one of the most expensive malignancies. The objective of this study was to identify reproducible prognostic miRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets. METHODS: NMIBC patient tumors from the New Hampshire Population Cohort (n=178) and Dartmouth Hitchcock Medical Center (n=38) were assayed for ∼800 miRNAs. Recurrence free survival (RFS) analyses using a multivariable model adjusted for sex, age, multiplicity, tumor size, stage, and grade were performed. Urine and plasma samples were obtained from available patients from the validation cohort and analyzed for miRNA expression. Lin28, a known negative regulator of Let-7f-5p, Lin28 primers and small molecule inhibitor Lin28 1632 were obtained and assayed using RT-PCR, cell viability, and scratch assays in NMIBC cell line HTB-2. RESULTS: miRNA Let-7f-5p showed the strongest association with recurrence across both the NH population cohort (p=0.039) and the DHMC TaHG/T1 cohort (p=0.065). Survival analyses stratified by median Let-7f-5p expression confirmed longer RFS in the patients with high Let-7f-5p for both discovery and validation cohorts (p=0.011 and 0.065; Figure 1A/B). Let-7f-5p was found to have potential clinical utility as a biomarker, and levels in urine and plasma were both found to be significantly correlated with levels in tumor tissue (P=0.0004 and 0.014, respectively). Finally, inhibition of Lin28 with Lin28 1632 significantly increased levels of Let-7f-5p expression (p=0.0003; Figure 1C) and led to significant inhibition of viability and migration of HTB-2 cells (both p<0.0001; Figures 1D/E). CONCLUSIONS: In this study, we have identified Let-7f-5p as a novel miRNA biomarker of recurrence in NMIBC tumors, and show that patients with high Let-7f-5p have longer RFS. We further show that targeting Lin28, a negative regulator of Let-7f-5p, represents a novel therapeutic opportunity in NMIBC. Source of Funding: Grant numbers R21CA182659, K07CA102327, CA182659, LM009012, GM103506 and GM103534, RR024475, RR028309, CA102327, CA121382, CA141017, CA099500, CA82354, CA078609, ES00002, 5P42ES05947, RR018787, and ES07373 from the National Cancer Institute, NIH, from the National Institute of Environmental Health Sciences, NIH, the National Center for Research Resources, NIH, and the National Institute of General Medical Sciences, NIH. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e226-e226 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kevin Shee* More articles by this author Carmen J Marsit More articles by this author Alan R Schned More articles by this author Jason Pettus More articles by this author David A Armstrong More articles by this author Margaret R Karagas More articles by this author Todd W Miller More articles by this author John D Seigne More articles by this author Angeline S Andrew More articles by this author Expand All Advertisement PDF downloadLoading ...