Wang Tao, Ding Fei, Sun Kai
Department of Oncology, Lanzhou University Second Hospital, Lanzhou, China.
Department of Obstetrics and Gynecology, Gansu Provincial Maternal and Child Healthcare Hospital, Lanzhou, China.
Front Genet. 2025 Aug 14;16:1527907. doi: 10.3389/fgene.2025.1527907. eCollection 2025.
Bladder urothelial carcinoma (BLCA) represents a highly malignant neoplasm with significant clinical challenges. Necroptosis, a programmed form of cell death, exhibits dual regulatory functions in both tumor immunomodulation and oncogenesis. The precise mechanistic involvement of necroptosis-related genes (NRGs) in BLCA pathogenesis remains poorly characterized, prompting our systematic investigation of their potential biological and clinical significance.
We performed comprehensive bioinformatics analyses utilizing integrated datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, we curated 159 NRGs and subsequently identified 25 differentially expressed genes functionally implicated in necrotic cell death and extrinsic apoptotic pathways, specifically including influenza A signaling, NOD-like receptor cascades, and related biological processes. Univariate Cox proportional hazards modeling coupled with LASSO regression analysis revealed five prognostically significant NRGs ( and ). Based on these genes, we developed a robust prognostic model that can stratify patients into high- and low-risk categories, each exhibiting distinct survival outcomes. This model demonstrated moderate accuracy in prognosis prediction. Immunohistochemical validation in BLCA specimens confirmed dysregulated expression patterns of these five NRGs. Additional analyses uncovered significant correlations between NRG expression profiles and various immunological parameters, including immune cell infiltration patterns and immune checkpoint molecule expression.
Our study delineates a novel five-gene NRG signature with robust prognostic value in BLCA. These gene determinants appear to critically influence both tumor progression and immune microenvironment, thereby representing promising candidates for therapeutic targeting and future mechanistic exploration in bladder cancer biology.
膀胱尿路上皮癌（BLCA）是一种具有重大临床挑战的高度恶性肿瘤。坏死性凋亡是一种程序性细胞死亡形式，在肿瘤免疫调节和肿瘤发生中均表现出双重调节功能。坏死性凋亡相关基因（NRGs）在BLCA发病机制中的精确机制参与仍不清楚，促使我们对其潜在的生物学和临床意义进行系统研究。
我们利用来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的整合数据集进行了全面的生物信息学分析。通过京都基因与基因组百科全书（KEGG）通路注释，我们整理了159个NRGs，随后鉴定出25个在坏死性细胞死亡和外源性凋亡途径中具有功能牵连的差异表达基因，具体包括甲型流感信号传导、NOD样受体级联反应及相关生物学过程。单变量Cox比例风险模型与LASSO回归分析相结合，揭示了五个具有预后意义的NRGs（和）。基于这些基因，我们开发了一个强大的预后模型，该模型可以将患者分为高风险和低风险类别，每个类别都表现出不同的生存结果。该模型在预后预测中显示出中等准确性。BLCA标本中的免疫组织化学验证证实了这五个NRGs的表达模式失调。进一步的分析发现NRG表达谱与各种免疫参数之间存在显著相关性，包括免疫细胞浸润模式和免疫检查点分子表达。
我们的研究描绘了一种在BLCA中具有强大预后价值的新型五基因NRG特征。这些基因决定因素似乎对肿瘤进展和免疫微环境都有至关重要的影响，因此代表了膀胱癌生物学中治疗靶点和未来机制探索的有希望的候选者。
