Abstract 764P
Background
Due to its relapsing and progressive nature, the treatment of patients with muscle invasive bladder carcinoma (MIBC) remains challenging. Neoadjuvant administration of cisplatin-containing chemotherapy (NAC) is recommended before cystectomy to lower the risk of recurrence, but the survival benefits are impaired in up to 50 % of the patients due to chemoresistance and patient fragility. RNA-binding motif protein 3 (RBM3), a RNA- and DNA-binding protein, has emerged as a candidate biomarker of survival and improved chemotherapy response. Herein, the role of RBM3 in MIBC was evaluated in the pre-clinical as well as the clinical setting.
Methods
The immunohistochemical expression of RBM3 was analyzed in tissue microarrays with paired transurethral (TURB) specimens, cystectomy specimens and lymph node metastases from 145 patients, out of whom 65 had received NAC. T24 bladder cancer cell lines were transfected with anti-RBM3 siRNA in vitro and the influence on cell viability following chemotherapy was assessed. Next generation RNA sequencing was performed to compare gene expression between T24 cells with siRNA-downregulated RBM3 and control cells.
Results
The expression of RBM3 was consistent between the different types of specimens and a high RBM3 expression correlated with a shorter time to recurrence, independently of NAC. siRNA-mediated suppression of RBM3 rendered the T24 cells less sensitive to chemotherapy in vitro. RNA sequencing revealed that RBM3 is linked to processes associated with cell cycle progression and cell division, including up- and downregulation of crucial cell cycle checkpoint proteins. New candidate biomarkers coupled to cellular proliferation were found, e.g. PDS5 cohesion associated factor A (PDS5A) and proline-rich protein 11 (PRR11). Interestingly, similar results were observed for pancreatic cancer cells, suggesting tumor agnostic mechanisms.
Conclusions
These findings highlight RBM3 as a potentially prognostic and predictive biomarker in the primary as well as the metastatic setting of MIBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Swedish Cancer Society (grant number 2016/483), the Swedish Research Council (grant number 2015-03598), the Mrs Berta Kamprad Foundation (grant number 2016-21), Governmental Funding of Clinical Research within the National Health Service (ALF) (grant number F 2014/354), Skåne University Hospital Funds and Donations and Lund University Faculty of Medicine.
Disclosure
All authors have declared no conflicts of interest.