Wei Meng1, Jason Efstathiou2, Rajbir Singh1, Joseph McElroy3, Stefano Volinia4, Ri Cui5, Ahmed Ibrahim6, Benjamin Johnson1, Nirmala Gupta7, Satvam Mehta8, Huabao Wang9, Eric Miller1, Phuong Nguyen10, Jessica Fleming1, Chin-Lee Wu11, S Jaharul Haque1, William Shipley2, Arnab Chakravarti12. 1. Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio. 2. Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts. 3. Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio. 4. Università degli Studi di Ferrara, Ferrara, Italy. 5. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. 6. Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden; Division of Pharmaceutical Industries, National Research Centre, Dokki, Egypt. 7. Case Western Reserve University, Cleveland, Ohio. 8. The Ohio State University, Columbus, Ohio. 9. The Genomics Shared Resource, The Ohio State University Wexner Medical Center, Columbus, Ohio. 10. Department of Radiation Oncology, Ohio Valley Medical Center, Wheeling, West Virginia. 11. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. 12. Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address: chakravarti.7@osu.edu.
Abstract
PURPOSE: Trimodality therapy with maximal transurethral resection of bladder tumor and definitive chemoradiation reserving cystectomy for salvage of local recurrence is an accepted treatment alternative to upfront cystectomy for selected patients with muscle-invasive bladder cancer. There is a need for molecular biomarkers to predict which patients will respond to bladder preservation therapy. METHODS AND MATERIALS: We sought to identify biomarkers with the ability to predict response to chemoradiation and survival after selective bladder preservation therapy in a cohort of 40 patients using a microRNA profiling approach. In vitro experiments were performed using transitional cell carcinoma lines CRL1749, HTB5, and HTB4. RESULTS: We identified a panel of microRNAs associated with overall survival in our bladder preservation cohort and in the TCGA cohort. We also identified several microRNAs, including miR-23a and miR-27a, microRNAs of the miR-23a cluster, to be suggestively associated with complete response to chemoradiation therapy. The microRNAs were significantly associated with overall survival in The Cancer Genome Atlas cohort. In vitro studies suggest that the functional roles of miR-23a and miR-27a involve targeting the SFRP1 protein, a negative regulator of the Wnt signaling pathway. The upregulation of β-catenin in the Wnt signaling pathway mediated proliferation, migration, invasion, and sensitivity to radiation and cisplatin treatment in bladder cancer cells. CONCLUSIONS: Our results indicate that miR-23a and miR-27a act as oncomirs, and once independently validated, they may help appropriately triage selected bladder cancer patients to individualize treatment.
PURPOSE: Trimodality therapy with maximal transurethral resection of bladder tumor and definitive chemoradiation reserving cystectomy for salvage of local recurrence is an accepted treatment alternative to upfront cystectomy for selected patients with muscle-invasive bladder cancer. There is a need for molecular biomarkers to predict which patients will respond to bladder preservation therapy. METHODS AND MATERIALS: We sought to identify biomarkers with the ability to predict response to chemoradiation and survival after selective bladder preservation therapy in a cohort of 40 patients using a microRNA profiling approach. In vitro experiments were performed using transitional cell carcinoma lines CRL1749, HTB5, and HTB4. RESULTS: We identified a panel of microRNAs associated with overall survival in our bladder preservation cohort and in the TCGA cohort. We also identified several microRNAs, including miR-23a and miR-27a, microRNAs of the miR-23a cluster, to be suggestively associated with complete response to chemoradiation therapy. The microRNAs were significantly associated with overall survival in The Cancer Genome Atlas cohort. In vitro studies suggest that the functional roles of miR-23a and miR-27a involve targeting the SFRP1 protein, a negative regulator of the Wnt signaling pathway. The upregulation of β-catenin in the Wnt signaling pathway mediated proliferation, migration, invasion, and sensitivity to radiation and cisplatin treatment in bladder cancer cells. CONCLUSIONS: Our results indicate that miR-23a and miR-27a act as oncomirs, and once independently validated, they may help appropriately triage selected bladder cancerpatients to individualize treatment.
Authors: Victor M Schuettfort; Benjamin Pradere; Fahad Quhal; Hadi Mostafaei; Ekaterina Laukhtina; Keiichiro Mori; Reza Sari Motlagh; Margit Fisch; David D'Andrea; Michael Rink; Paolo Gontero; Francesco Soria; Shahrokh F Shariat Journal: World J Urol Date: 2020-09-29 Impact factor: 4.226