The Second Affiliated Hospital, Hengyang Medical School, 34706University of South China, Hengyang, China.
504354The Third Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
Technol Cancer Res Treat. 2022 Jan-Dec;21:15330338221090093. doi: 10.1177/15330338221090093.
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. 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. 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. 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.
膀胱癌是美国男性中第四大常见恶性肿瘤。异常的选择性剪接（AS）事件参与了癌症的发生，但 AS 与膀胱癌之间的关联仍不清楚。本研究旨在构建基于 AS 的预后特征，并阐明肿瘤免疫微环境（TIME）以及对免疫治疗和化疗的反应在膀胱癌中的作用。使用单变量 Cox 回归分析检测与预后相关的 AS 事件。使用最小绝对收缩和选择算子（LASSO）和多变量 Cox 分析构建预后特征。进行 Kaplan-Meier 生存分析、多变量 Cox 回归分析和接受者操作特征（ROC）曲线验证预后特征。然后，使用 ESTIMATE 和 TIMER 数据库搜索 Estimation of Stromal and Immune cells in MAlignant Tumors tissues using Expression data (ESTIMATE) 和 tumor immune estimation resource (TIMER) 数据库，并使用单样本基因集富集分析（ssGSEA）算法和 CIBERSORT 方法揭示膀胱癌中 TIME 的背景。使用 Tumor Immune Dysfunction and Exclusion (TIDE) 网络工具和 pRRophetic 算法预测免疫治疗和化疗的反应。最后，我们构建了剪接因子（SFs）与生存相关 AS 事件之间的相关网络。总共鉴定出 4684 个与膀胱癌患者总生存期显著相关的 AS 事件。建立了 8 个膀胱癌预后特征，并构建了临床生存预测模型。此外，综合预后特征与免疫浸润以及免疫治疗和化疗的反应密切相关。此外，相关性鉴定出 EIF3A、DDX21、SDE2、TNPO1 和 RNF40 作为枢纽 SFs，功能分析发现泛素介导的蛋白酶体降解与生存相关 AS 事件最显著相关。 我们的研究结果突出了 AS 对膀胱癌患者的预后价值，并揭示了 AS 事件在 TIME 以及免疫治疗和化疗反应中的关键作用，这可能对患者管理和治疗具有重要意义。
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