Liu Ting, Pu Jingjing, Theil Sandra, Liu Yanxia, Jiang Liping, Liu Hongde, Maciaczyk Jarek, Schmidt-Wolf Ingo G H, Walter Jochen, Sharma Amit
Department of Geriatrics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Department of Integrated Oncology, Center for Integrated Oncology (CIO) Bonn, University Hospital Bonn, 53127, Bonn, Germany.
Sci Rep. 2025 Jul 1;15(1):21535. doi: 10.1038/s41598-025-08000-7.
Tumor suppressor genes (TSGs) are critical regulators of cellular homeostasis and are extensively studied in cancer biology. However, their roles in neurodegenerative diseases, particularly Alzheimer's disease (AD), remain poorly understood. Recent evidence of an inverse association between cancer and AD suggests the existence of shared molecular mechanisms. We conducted an integrative analysis to identify TSGs with potential involvement in both AD and glioblastoma (GBM), using Mendelian randomization, transcriptomic profiling (bulk and single-cell RNA-seq), cell-cell communication inference, and in vitro validation. Among 1,217 TSGs screened, TNFRSF12A was consistently dysregulated in both GBM and AD datasets. Further analysis revealed its association with immune-related pathways and transcriptional programs relevant to both diseases. Knockdown of TNFRSF12A in glioma cells altered the expression of genes associated with amyloid precursor protein (APP) processing and Wnt signaling pathways. This study identifies TNFRSF12A as a cross-disease candidate gene in GBM and AD, based on transcriptomic convergence and partial functional validation. Our findings suggest that TSGs may contribute to shared molecular programs in neurodegeneration and cancer, and warrant further mechanistic investigation.
肿瘤抑制基因（TSGs）是细胞稳态的关键调节因子，在癌症生物学中得到了广泛研究。然而，它们在神经退行性疾病，尤其是阿尔茨海默病（AD）中的作用仍知之甚少。最近癌症与AD之间存在负相关的证据表明存在共同的分子机制。我们进行了一项综合分析，利用孟德尔随机化、转录组分析（批量和单细胞RNA测序）、细胞间通讯推断和体外验证，来确定可能同时参与AD和胶质母细胞瘤（GBM）的TSGs。在筛选的1217个TSGs中，TNFRSF12A在GBM和AD数据集中均持续失调。进一步分析揭示了它与两种疾病相关的免疫相关途径和转录程序的关联。在胶质瘤细胞中敲低TNFRSF12A会改变与淀粉样前体蛋白（APP）加工和Wnt信号通路相关的基因表达。基于转录组趋同和部分功能验证，本研究将TNFRSF12A确定为GBM和AD中的跨疾病候选基因。我们的研究结果表明，TSGs可能促成神经退行性变和癌症中的共同分子程序，值得进一步进行机制研究。
