Integrative Transcriptome Profiling Reveals SKA3 as a Novel Prognostic Marker in Non-Muscle Invasive Bladder Cancer

SIMPLE SUMMARY: Approximately 80% of all new bladder cancer patients are diagnosed with non-muscle invasive bladder cancer. However, about 15% of them progress to muscle-invasive bladder cancer, which is associated with poor prognosis. As these diseases are highly heterogeneous, the identification of an accurate prognostic biomarker for them has been challenging. In the present study, our aims were to compare cancerous and normal adjacent bladder tissues excised from patients in various cohorts and endeavor to detect differentially expressed genes known to be upregulated exclusively in patients at high risk of bladder cancer progression. Through various molecular methods, we found that the expression level of the cell cycle-regulating SKA3 gene was markedly increased in patients with worse prognosis and high progression risk. Hence, SKA3 is a viable predictive marker for bladder cancer progression and its inhibition could constitute part of a novel therapy that improves the prognosis of this disease. ABSTRACT: Approximately 80% of all new bladder cancer patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). However, approximately 15% of them progress to muscle-invasive bladder cancer (MIBC), for which prognosis is poor. The current study aimed to improve diagnostic accuracy associated with clinical outcomes in NMIBC patients. Nevertheless, it has been challenging to identify molecular biomarkers that accurately predict MIBC progression because this disease is complex and heterogeneous. Through integrative transcriptome profiling, we showed that high SKA3 expression is associated with poor clinical outcomes and MIBC progression. We performed RNA sequencing on human tumor tissues to identify candidate biomarkers in NMIBC. We then selected genes with prognostic significance by analyzing public datasets from multiple cohorts of bladder cancer patients. We found that SKA3 was associated with NMIBC pathophysiology and poor survival. We analyzed public single-cell RNA-sequencing (scRNA-seq) data for bladder cancer to dissect transcriptional tumor heterogeneity. SKA3 was expressed in an epithelial cell subpopulation expressing genes regulating the cell cycle. Knockdown experiments confirmed that SKA3 promotes bladder cancer cell proliferation by accelerating G2/M transition. Hence, SKA3 is a new prognostic marker for predicting NMIBC progression. Its inhibition could form part of a novel treatment lowering the probability of bladder cancer progression.