Xie Ruiyan, Xie Ming, Zhu Litong, Chiu Joanne W Y, Lam Wayne, Yap Desmond Y H
Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Front Pharmacol. 2022 Jul 19;13:930951. doi: 10.3389/fphar.2022.930951. eCollection 2022.
The role of pyroptosis and its effects on tumor-infiltrating cells (TICs) in the pathogenesis and treatment outcomes of patients with bladder urothelial carcinoma (BLCA) remains unclear. We conducted a bioinformatics analysis on the pyroptosis-related genes (PRGs) and TICs using data from public domains, and evaluated their impact on the pathogenesis and clinical outcomes of BLCA patients. A risk score based on PRGs and a prognostic risk model that incorporated patient demographics, tumor characteristics, and differentially expressed genes (DEGs) were developed. Twenty-three DEGs of 52 PRGs were identified in BLCA and normal samples from the TCGA database. Missense mutations and single nucleotide polymorphisms in PRGs are the most common genetic abnormalities. Patients with high PRG risk scores showed an inferior survival compared to those with low risk scores. The prognostic risk model based on patient demographics, tumor characteristics, and DEGs showed good predictive values for patient survival at 1, 3, and 5 years in BLCA patients. Caspase-8 (CASP8) was the only intersection gene of the prognostic genes, DEGs, and different genes expressed in tissue. Patients with a high CASP8 expression had improved survival, and an increased CASP8 expression level was observed in activated CD4 memory T cells, follicular T helper cells, resting NK cells, M0 macrophages, and activated dendritic cells. CASP8 expression also showed a positive correlation with the IL7R expression-a key cell marker of CD4 memory T cells. CASP8 expression also showed correlations with immune checkpoints (PDCD1, CD274, and CTLA4) and response to immune checkpoint inhibitors. Our data suggest that PRGs, especially CASP8, showed strong associations with patient outcomes and TICs in BLCA. If validated, these results could potentially aid in the prognostication and guide treatment in BLCA patients.
细胞焦亡在膀胱尿路上皮癌（BLCA）患者的发病机制和治疗结果中的作用及其对肿瘤浸润细胞（TICs）的影响仍不清楚。我们使用来自公共领域的数据对细胞焦亡相关基因（PRGs）和TICs进行了生物信息学分析，并评估了它们对BLCA患者发病机制和临床结果的影响。基于PRGs开发了一个风险评分以及一个纳入患者人口统计学、肿瘤特征和差异表达基因（DEGs）的预后风险模型。在TCGA数据库的BLCA和正常样本中鉴定出52个PRGs中的23个DEGs。PRGs中的错义突变和单核苷酸多态性是最常见的基因异常。PRG风险评分高的患者与低风险评分的患者相比，生存率较低。基于患者人口统计学、肿瘤特征和DEGs的预后风险模型对BLCA患者1年、3年和5年的生存率显示出良好的预测价值。半胱天冬酶8（CASP8）是预后基因、DEGs和组织中表达的不同基因的唯一交集基因。CASP8表达高的患者生存率提高，并且在活化的CD4记忆T细胞、滤泡辅助性T细胞、静息自然杀伤细胞、M0巨噬细胞和活化的树突状细胞中观察到CASP8表达水平升高。CASP8表达还与IL7R表达呈正相关，IL7R是CD4记忆T细胞的关键细胞标志物。CASP8表达还与免疫检查点（PDCD1、CD274和CTLA4）以及对免疫检查点抑制剂的反应相关。我们的数据表明，PRGs，尤其是CASP8，与BLCA患者的预后和TICs密切相关。如果得到验证，这些结果可能有助于BLCA患者的预后评估并指导治疗。
