Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer : longitudinal expression, transcriptome-level effects and modulation of chemosensitivity
Wahlin, Sara LU ; Boman, Karolina LU ; Moran, Bruce ; Nodin, Björn LU ; Gallagher, William M. ; Karnevi, Emelie LU and Jirström, Karin LU
(2022)
In BMC Cancer
22(1).
- Abstract
Background: The 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. Methods: RBM3 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... (More)
Background: The 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. Methods: RBM3 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. Results: RBM3 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. Conclusions: The 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.
(Less)
- author
- Wahlin, Sara
LU
; Boman, Karolina
LU
; Moran, Bruce
; Nodin, Björn
LU
; Gallagher, William M.
; Karnevi, Emelie
LU
and Jirström, Karin
LU
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Biomarker, Cell cycle, Chemotherapy response, Muscle-invasive bladder cancer, Prediction, RBM3
- in
- BMC Cancer
- volume
- 22
- issue
- 1
- article number
- 131
- publisher
- BioMed Central (BMC)
- external identifiers
-
- scopus:85124061106
- pmid:35109796
- ISSN
- 1471-2407
- DOI
- 10.1186/s12885-021-09168-7
- language
- English
- LU publication?
- yes
- id
- 1412ab44-4f68-4207-bf93-7dbd6fdf867f
- date added to LUP
- 2022-04-07 12:31:41
- date last changed
- 2024-06-21 10:08:09
@article{1412ab44-4f68-4207-bf93-7dbd6fdf867f,
abstract = {{<p>Background: The 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. Methods: RBM3 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. Results: RBM3 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 G<sub>1</sub>/S-phase transition, and initiation of DNA replication. Furthermore, siRBM3-transfected T24 cells displayed an accumulation of cells residing in the G<sub>1</sub>-phase as well as altered levels of recognised regulators of G<sub>1</sub>-phase progression, including Cyclin D1/CDK4 and CDK2. Conclusions: The 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.</p>}},
author = {{Wahlin, Sara and Boman, Karolina and Moran, Bruce and Nodin, Björn and Gallagher, William M. and Karnevi, Emelie and Jirström, Karin}},
issn = {{1471-2407}},
keywords = {{Biomarker; Cell cycle; Chemotherapy response; Muscle-invasive bladder cancer; Prediction; RBM3}},
language = {{eng}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{BMC Cancer}},
title = {{Pre-clinical and clinical studies on the role of RBM3 in muscle-invasive bladder cancer : longitudinal expression, transcriptome-level effects and modulation of chemosensitivity}},
url = {{http://dx.doi.org/10.1186/s12885-021-09168-7}},
doi = {{10.1186/s12885-021-09168-7}},
volume = {{22}},
year = {{2022}},
}