Abstract
Urothelial bladder cancer (UBC) are classified into luminal and basal subtypes showing distinct molecular features and clinical behaviour. Recent in silico data have proposed the activation on the Signal Transducer and Activator of Transcription 3 (STAT3) as relevant transcription factor in UBC. To answer this question, we have combined the retrospective analysis of clinical samples, functional assays on cell lines, interrogation of public UBC datasets and a murine model of basal-type UBC. Immunohistochemistry on a retrospective UBC cohort uncovered that STAT3 Y705 phosphorylation (pSTAT3) is significantly increased in infiltrating basal-type UBC compared to luminal UBC. In vitro, STAT3 silencing in UBC cell lines significantly reduced tumor cell viability and invasion. Gene expression profile of UBC cell lines combined with the analysis of the Cancer Genome Atlas (TCGA) and GSE32894 UBC datasets showed that increased expression of a set of STAT3 targets predicts basal-type, propensity to local progression and worse prognosis. MYC and FOSL1 represent relevant STAT3 downstream targets, as validated by their co-localization in pSTAT3+ UBC cancer cells. These findings were largely reproduced in the BBN-induced murine model of basal-type UBC. Of note, FOSL1 protein resulted strongly expressed in the non-papillary UBC pathway and FOSL1-regulated transcripts were significantly enriched in the transition from NMIBC to MIBC, as indicated by the interrogation of the GSE32894 dataset. The blockade of the STAT3 pathway might represent a novel treatment option for these neoplasms. Monitoring pSTAT3 and the downstream targets, particularly FOSL1, could provide meaningful levels of UBC stratification.
Highlights
Bladder cancer (BC) is the fourth most common carcinoma among men in the Western world ranking 13th in terms of mortality rate [1]
20–30% of Urothelial bladder cancer (UBC) are diagnosed as advanced muscle-invasive forms (MIBCs), whereas the remaining 70–80% are non-muscle invasive (NMIBCs), the latter mainly corresponding to low grade superficial papillary tumors (LGPBCs) [1]
Signal Transducer and Activator of Transcription 3 (STAT3) Is Activated in the Early Phases of UBC Invasion
Summary
Bladder cancer (BC) is the fourth most common carcinoma among men in the Western world ranking 13th in terms of mortality rate [1]. BC is largely represented by urothelial carcinoma (UBC) [2]. 20–30% of UBC are diagnosed as advanced muscle-invasive forms (MIBCs), whereas the remaining 70–80% are non-muscle invasive (NMIBCs), the latter mainly corresponding to low grade superficial papillary tumors (LGPBCs) [1]. While LGPBCs generally have a good prognosis and an excellent survival rate, the outcome of advanced MIBCs remains very poor. A minor fraction of NMIBCs eventually evolve to MIBC, a switch that cannot be predicted by biomarkers currently used in the clinical practice. Treatment approaches for MIBC are limited to radical cystectomy (with or without neo-adjuvant chemotherapy) and urinary diversion, but only 40%
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