Prognostic significance of replication protein A (RPA) expression levels in bladder urothelial carcinoma

Abstract

( ρ = 0.354, P < 0.001 and ρ = 0.934, P < 0.001).• In survival analysis of the entire cohort decreased RPA2 and RPA1 correlated with a lesser probability of survival ( P < 0.001 and P = 0.018). In non-muscle-invasive tumours (Ta-T1) only lower RPA2 ( P < 0.001) was correlated with shortened survival, whereas in muscle-invasive tumours (T2-T4) decreased RPA2 and RPA1 expression levels were associated with adverse prognosis ( P = 0.035 and P = 0.042, respectively).• In multivariate survival analysis of the entire cohort and in non-muscle-invasive cases RPA2 expression remained significant, even when adjustment for cyclin D1 expression was applied. CONCLUSIONS• RPA1 and RPA2 overexpression seems to be more important during early T-categories of bladder carcinogenesis. Showing similar kinetics with cyclin D1.• RPA2 expression emerges as a valuable marker of favourable prognosis in the entire cohort and in non-muscle-invasive tumours, supplementing the information obtained by standard clinicopathological prognosticators. KEYWORDS RPA, immunoexpression, bladder urothelial carcinomaWhat's known on the subject? and What does the study add? The prognostic utility of cyclin D1 in non-muscle and muscle-invasive urothelial bladder carcinomas has already been examined by our group and our investigators previously. Moreover, recent investigations have shown that RPA protein expression may be implicated in the pathogenesis of various malignant tumours. In this study, RPA1 and RPA2 overexpression seems to be more important during early T-categories of bladder carcinogenesis, showing similar kinetics with cyclin D1, whereas RPA2 expression emerges as a valuable marker of favourable prognosis in the entire cohort and in non-muscle-invasive tumours, supplementing the information obtained by standard clinicopathological prognosticators. OBJECTIVE• To elucidate the role of replication protein A (RPA) in both superficial (Ta-T1) and muscle-invasive (T2-T4) urothelial carcinomas (UCs), investigating its potential prognostic usefulness. PATIENTS AND METHODS• Paraffin-embedded tissue from 156 patients with bladder UC was immunostained for RPA1 and RPA2. RESULTS• RPA1 and RPA2 labelling indexes (LIs) decreased with increasing histological grade (both P < 0.001) and T-category in the entire cohort ( P = 0.008 and P < 0.001, respectively) and in muscle-invasive carcinomas ( P = 0.014 and P = 0.012, respectively).• RPA1 expression was positively correlated with RPA2 (Spearman's correlation coefficient ρ = 0.309, P < 0.001). Both RPA1 and RPA2 LIs were positively correlated with cyclin D1 expression

Transcriptional Signatures of Ral GTPase Are Associated with Aggressive Clinicopathologic Characteristics in Human Cancer

“…Clusterin has substantial literature in bladder cancer as an antiapoptotic protein, both as a biomarker for disease aggression and, when inhibited, as a chemosensitizing agent to the key chemotherapeutic drug, gemcitabine; in prostate cancer, an inhibitor of clusterin, custirsen (OGX-011) has shown promise as a chemosensitizing agent in clinical trials castration resistant disease (48). Overexpression of replication protein A1 (RPA1), which we found to be lower in Ral signature positive cells, has been recently demonstrated to be a positive prognostic factor in bladder cancer (49), which correlates our signature findings. The L1CAM adhesion molecule, higher in signature positive cells, has an extensive literature in invasion and metastasis (50) and may be involved in cooperative signaling with the aforementioned CD24.…”

Replication protein A: a reliable biologic marker of prognostic and therapeutic value in human astrocytic tumors

“…The observed nuclear abundance of these molecules is in accordance with previous studies performed in breast [22], colon [23], and urothelial bladder [24] cancer, as well as with a cell fractionation study [25]. Furthermore, in agreement with these previous reports in other tissues [22][23][24], a widespread overexpression of the RPAs was noticed only in tumor cells as compared with normal tissue. The same applies to the expression of cyclins D2 and D3, whereas higher cyclin D1 expression has been recently observed in astrogliosis as compared with low-grade astrocytomas [26].…”

“…However, treatment-related variables were accounted for in multivariate analysis and did not affect the prognostic significance of RPA2. Analogous findings have also been reported in bladder [24] and colorectal cancer [23].…”

“…According to our results, there was a positive correlation between the expression patterns of RPA1 and RPA2 as well as between the expression of each of these RPA subunits and the expression of cyclins D2 and D3. The significant associations observed between these molecules possibly reflect their similar kinetics, a finding that has also been reported previously for cyclin D1 and RPA proteins in urothelial bladder cancer [24].…”

Variable Number Tandem Repeats mediate the expression of proximal genes

“…The RPA2 gene product is part of the Replication Protein A complex involved in DNA damage checkpointing 62 . Its over-expression is identified as a prognostic marker for colon cancer 63 and bladder cancers 64 . A VNTR that overlapped the Transcription Start Site (TSS) of RP2A with lower VNTR length showed 1.9-fold higher expression of RPA2 in multiple tissues including colon (Supp.…”