Affiliations: [a] Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA | [b] Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA | [c] Department of Environmental Health and of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
Correspondence:
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Corresponding author: Angeline S. Andrew, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, One Medical Center Drive, 7936 Rubin Building, Lebanon, NH, 03756, USA. Tel.: +1 603 653 9019; E-mail: [email protected].
Abstract: BACKGROUND: Among patients diagnosed with non-muscle invasive bladder cancer (NMIBC), 30% to 70% experience recurrences within 6 to 12 years of diagnosis. The need to screen for these events every 3 to 6 months and ultimately annually by cystoscopy makes bladder cancer one of the most expensive malignancies to manage. OBJECTIVE: The purpose of this study was to identify reproducible prognostic microRNAs in resected non-muscle invasive bladder tumor tissue that are predictive of the recurrent tumor phenotype as potential biomarkers and molecular therapeutic targets. METHODS: Two independent cohorts of NMIBC patients were analyzed using a biomarker discovery and validation approach, respectively. RESULTS: miRNA Let-7f-5p showed the strongest association with recurrence across both cohorts. Let-7f-5p levels in urine and plasma were both found to be significantly correlated with levels in tumor tissue. We assessed the therapeutic potential of targeting Lin28, a negative regulator of Let-7f-5p, with small-molecule inhibitor C1632. Lin28 inhibition significantly increased levels of Let-7f-5p expression and led to significant inhibition of viability and migration of HTB-2 cells. CONCLUSIONS: We have identified Let-7f-5p as a miRNA biomarker of recurrence in NMIBC tumors. We further demonstrate that targeting Lin28, a negative regulator of Let-7f-5p, represents a novel potential therapeutic opportunity in NMIBC.
