Immunotherapeutic Significance of a Prognostic Alternative Splicing Signature in Bladder Cancer

Abstract

Objectives: Bladder cancer is the fourth most common malignancy in men in the United States. Aberrant alternative splicing (AS) events are involved in the carcinogenesis, but the association between AS and bladder cancer remains unclear. This study aimed to construct an AS-based prognostic signature and elucidate the role of the tumor immune microenvironment (TIME) and the response to immunotherapy and chemotherapy in bladder cancer. Methods: Univariate Cox regression analysis was performed to detect prognosis-related AS events. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses were employed to build prognostic signatures. Kaplan–Meier survival analysis, multivariate Cox regression analysis, and receiver operating characteristic (ROC) curves were conducted to validate the prognostic signatures. Then, the Estimation of Stromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) and tumor immune estimation resource (TIMER) databases were searched and the single-sample gene set enrichment analysis (ssGSEA) algorithm and CIBERSORT method were performed to uncover the context of TIME in bladder cancer. The Tumor Immune Dysfunction and Exclusion (TIDE) web tool and pRRophetic algorithm were used to predict the response to immunotherapy and chemotherapy. Finally, we constructed a correlation network between splicing factors (SFs) and survival-related AS events. Results: A total of 4684 AS events were significantly associated with overall survival in patients with bladder cancer. Eight prognostic signatures of bladder cancer were established, and a clinical survival prediction model was built. In addition, the consolidated prognostic signature was closely related to immune infiltration and the response to immunotherapy and chemotherapy. Furthermore, the correlation identified EIF3A, DDX21, SDE2, TNPO1, and RNF40 as hub SFs, and function analysis found ubiquitin-mediated proteolysis is correlated most significantly with survival-associated AS events. Conclusion: Our findings highlight the prognostic value of AS for patients with bladder cancer and reveal pivotal players of AS events in the context of TIME and the response to immunotherapy and chemotherapy, which may be important for patient management and treatment.

A Novel m7G-Related Genes-Based Signature with Prognostic Value and Predictive Ability to Select Patients Responsive to Personalized Treatment Strategies in Bladder Cancer

“…METTL1 is highly expressed in BLCA tissues, and its expression is positively correlated with a poor prognosis of BLCA patients [ 21 ]. Except for METTL1 and WDR4, other m7G-related genes were also investigated in previous studies [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. The stability and translation of CCNB1 are required for specific tRNA m7G methylation, and CCNB1 favors a progressing development in BLCA [ 24 , 25 ].…”

“…Knockdown of PNP suppresses the cell activity and induces apoptosis in BLCA [ 38 ]. TNPO1 regulates the alternative splicing in BLCA [ 39 ]. Similar to TNPO1, LENG8 is an alternative splicing-associated prognostic biomarker in kidney renal clear cell carcinoma patients [ 40 ].…”