The results from this study show that reduced RBM3 expression is significantly associated with more aggressive tumours and an independent predictor of reduced survival in patients with urothelial bladder cancer. Moreover, in patients with Ta and T1 tumours, reduced RBM3 expression correlated with a significantly shorter time to disease progression, despite the comparatively low number of events, and negative RBM3 expression was an independent predictor of a reduced 5-year overall survival. The association between RBM3 expression and a favorable clinical outcome has been demonstrated in several other cancer forms [6–10] but this is, to our knowledge, the first report of the prognostic impact of RBM3 expression in urothelial bladder cancer.
In this comparatively large study of retrospectively collected tumours from a prospective cohort of patients with urothelial bladder cancer, the most evident impact of RBM3 expression was seen for disease specific and overall survival, both in the full cohort and in subgroup analysis of patients with Ta and T1 tumours. The fact that the impact on progression-free survival in patients with Ta and T1 tumours was not as significant may be due to the lower number of events, and therefore, the association between RBM3 expression and tumour progression merits further validation in other cohorts. Notably, RBM3 expression was not associated with neither occurrence nor frequency of local recurrence. These findings may indeed indicate different, or even opposing, tumour biological roles for RBM3 in tumour initiation and progression of urothelial bladder cancer. Previous studies, e.g. in malignant melanoma, have demonstrated that the correlation between reduced RBM3 expression and overall survival was more evident than the correlation to recurrent disease . Speculatively, these findings could indicate that loss of RBM3 expression results in a tumour phenotype more prone to metastatic spread than local aggressiveness. RBM3 has previously been shown to be upregulated in neoplastic as compared to normal tissue [7, 9], which also seems to be true for urothelial bladder epithelium versus urothelial neoplasms (http://www.proteinatlas.org). While urothelial bladder cancer is in its nature a recurrent disease , a recurrence does not per se affect survival from the disease. It is therefore plausible to assume that tumours with high RBM3 expression may well recur, while loss of RBM3 expression will generate a disease more likely to muscle invasion and distant spread.
The precise functional mechanisms behind loss of RBM3 and a more aggressive tumour behaviour remain to be elucidated. However, in vitro models need to be designed and interpreted with the impact of RBM3 expression on clinical outcome in mind, and the previously demonstrated pro-tumourigenic properties for RBM3 in vitro, e.g. that siRNA mediated silencing of the gene renders cancer cells less proliferative [10, 13, 14], should not be interpreted as being contradictory to its association with a prolonged survival when expressed in human tumours.
In a translational context, further probing of the association between RBM3 and DNA integrity and repair, that has been demonstrated in epithelial ovarian cancer in vivo and in vitro , may give more insight into the mechanistic basis for the favourable prognostic impact of RBM3 expression, once a tumour has been established. The link between RBM3 expression and an attenuated DNA damage response not only fits with its previously demonstrated association with cisplatin sensitivity , but also its association with good prognosis, since a deficient DNA repair system may well decrease the capability of invasion and metastatic spread [15, 16]. Along this line, it would also be of interest to investigate the impact of RBM3 as a predictor of response to platinum-based chemotherapy, both in the neoadjuvant, adjuvant and palliative setting, cisplatin being one of the cornerstones in the medical treatment of bladder cancer [17–20]. Few molecular markers have proven to be efficient predictors of treament response, and none have been incorporated into clinical protocols. The question of the role of RBM3 as a marker for platinum sensitivity could not be addressed in the present study, as treatment data was lacking for the majority of the patients.
The clinical management of urothelial bladder cancer holds room for improvement. The monitoring is not only troublesome for the patients, but is also costly for the health care system. In fact, due to its high rate of recurrence and invasive monitoring requirements, urothelial bladder cancer has the highest lifetime treatment cost per patient of all cancers in the United States . Hence, the benefit of finding tools to better identify patients more likely to have, or being at risk of developing, muscle invasive and metastatic desease is evident. Here, we have demonstrated a stepwise reduced survival with decreasing levels of nuclear RBM3 expression. While the greatest impact on DSS and OS was seen for patients with tumours lacking RBM3 expression, an increased risk of disease progression was also observed in the patient group with intermediate expression. This observation, together with the strong correlation between loss of RBM3 and muscle invasive disease, indicates that loss of RBM3 expression may indeed be a marker of disease progression. Therefore, immunohistochemical assessment of RBM3 expression could prove to be a valuable tool to more accurately predict muscle invasion, even in suboptimal samples from transurethral resections of the bladder. Moreover, it would be of interest to evaluate whether immunocytochemical RBM3 expression could be a useful diagnostic tool for urine cytology samples, to distinguish between different low-grade urothelial neoplastic lesions, e.g. papillary neoplasms of low malignant potential and low-grade papillary urothelial carcinomas, entities with considerable cytologic-histologic discrepancies . While the findings in the present study are based on analyses of transitional cell carcinoma, it would also be of interest to examine RBM3 expression and its possible prognostic implications in other histological subtypes of bladder cancer, e.g. squamous cell carcinoma or adenocarcinoma.