Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer: longitudinal expression, transcriptome-level effects and modulation of chemosensitivity

BMC Cancer

Björn Nodin¹  Karolina Boman¹  Karin Jirström¹  Sara Wahlin¹  Emelie Karnevi¹  William M. Gallagher²  Bruce Moran² 

[1] Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden;UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Belfield, Dublin, Ireland;

关键词: RBM3;    Biomarker;    Cell cycle;    Prediction;    Chemotherapy response;    Muscle-invasive bladder cancer;   

DOI  :  10.1186/s12885-021-09168-7

来源: Springer

【 摘 要 】

BackgroundThe response to neoadjuvant cisplatin-based chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) is impaired in up to 50% of patients due to chemoresistance, with no predictive biomarkers in clinical use. The proto-oncogene RNA-binding motif protein 3 (RBM3) has emerged as a putative modulator of chemotherapy response in several solid tumours but has a hitherto unrecognized role in MIBC.MethodsRBM3 protein expression level in tumour cells was assessed via immunohistochemistry in paired transurethral resection of the bladder (TURB) specimens, cystectomy specimens and lymph node metastases from a consecutive cohort of 145 patients, 65 of whom were treated with NAC. Kaplan-Meier and Cox regression analyses were applied to estimate the impact of RBM3 expression on time to recurrence (TTR), cancer-specific survival (CSS), and overall survival (OS) in strata according to NAC treatment. The effect of siRNA-mediated silencing of RBM3 on chemosensitivity was examined in RT4 and T24 human bladder carcinoma cells in vitro. Cellular functions of RBM3 were assessed using RNA-sequencing and gene ontology analysis, followed by investigation of cell cycle distribution using flow cytometry.ResultsRBM3 protein expression was significantly higher in TURB compared to cystectomy specimens but showed consistency between primary tumours and lymph node metastases. Patients with high-tumour specific RBM3 expression treated with NAC had a significantly reduced risk of recurrence and a prolonged CSS and OS compared to NAC-untreated patients. In high-grade T24 carcinoma cells, which expressed higher RBM3 mRNA levels compared to RT4 cells, RBM3 silencing conferred a decreased sensitivity to cisplatin and gemcitabine. Transcriptomic analysis revealed potential involvement of RBM3 in facilitating cell cycle progression, in particular G1/S-phase transition, and initiation of DNA replication. Furthermore, siRBM3-transfected T24 cells displayed an accumulation of cells residing in the G1-phase as well as altered levels of recognised regulators of G1-phase progression, including Cyclin D1/CDK4 and CDK2.ConclusionsThe presented data highlight the potential value of RBM3 as a predictive biomarker of chemotherapy response in MIBC, which could, if prospectively validated, improve treatment stratification of patients with this aggressive disease.

【 授权许可】

CC BY