Immunological significance of alternative splicing prognostic signatures for bladder cancer

Bladder cancer (BLCA) is the most common malignant tumor in the genitourinary system, and the complex tumor microenvironment (TME) of BLCA is the main factor in its difficult treatment. Accumulated evidence supports that alternative splicing (AS) events frequently occur in cancer and are closely related to the TME. Therefore, there is an urgent need to comprehensively analyze the prognostic value of AS events in BLCA.

The clinical, transcriptome and AS data of BLCA were downloaded from the Cancer Genome Atlas database, and a Cox proportional hazard regression model and LASSO regression were used to establish a prognostic signature. Then, the prognostic value of the signature was verified by clinical survival status, clinicopathologic features, tumor immune microenvironment (TIME), and immune checkpoint. Next, we screened the AS-related genes with the largest expression differences between tumor and normal samples by gene differential expression analysis. Finally, the regulatory network of AS-splicing factors (SFs) was established to unravel the potential regulatory mechanism of AS events in BLCA.

A BLCA prognostic signature related to seven AS events was constructed, and the prognostic value of the signature was also verified from multiple perspectives. Moreover, there was significant abnormal expression of PTGER3, a gene implicated in AS events, the expression of which was associated with the survival, clinicopathological features, TIME, and immunotherapy of BLCA, suggesting that it has potential clinical application value. Furthermore, the AS-SF regulatory network indicated that splicing factors (PRPF39, LUC7L, HSPA8 and DDX21) might be potential biomarkers of BLCA.

Our study revealed the potential role of AS events in the prognosis, TIME and immunotherapy of BLCA and yielded new insights into the molecular mechanisms of and personalized immunotherapy for BLCA.