Men with prostate cancer are at increased risk of developing cognitive decline by the use of second‐generation androgen signaling inhibitors. To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high‐throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements‐cytoscape, and bioinformatic analyses employing Advaita® iPathwayGuide and DisGeNET for identification of disease‐related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real‐time polymerase chain reaction assay. Our systematic analysis of androgen deprivation‐associated genes involved multiple biological processes, including neuroactive ligand–receptor interaction, axon guidance, cytokine–cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma‐aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein–protein interaction network analysis highlighted the role of ligand‐gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene–disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type‐1 angiotensin II receptor, brain‐derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N‐methyl‐D‐aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5‐hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT‐mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.

中文翻译：

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配体门控离子通道作为前列腺癌患者 ADT 介导的认知能力下降的潜在生物标志物

使用第二代雄激素信号抑制剂后，患有前列腺癌的男性出现认知能力下降的风险增加。迄今为止，尚未确定能够区分雄激素剥夺疗法（ADT）下认知功能障碍高风险男性的可靠且敏感的生物标志物。我们使用模拟 ADT 的人类前列腺癌细胞培养模型进行高通量转录分析，使用最小的常见肿瘤学数据元素 - 细胞景观选择生物标志物，并使用 Advaita® iPathwayGuide 和 DisGeNET 进行生物信息分析来识别疾病相关基因关联。通过定量实时聚合酶链反应测定对脑神经元和神经胶质细胞进行基因验证分析。我们对雄激素剥夺相关基因的系统分析涉及多个生物过程，包括神经活性配体-受体相互作用、轴突引导、细胞因子-细胞因子受体相互作用以及代谢和癌症信号传导途径。与神经受体配体相互作用相关的基因，包括γ-氨基丁酸（GABA）A和B受体以及核核心蛋白，被确定为顶级上游调节因子。功能富集和蛋白质-蛋白质相互作用网络分析强调了配体门控离子通道（LGIC）及其受体在认知功能障碍中的作用。基因-疾病关联包括健忘、智力障碍、视觉空间缺陷、躁郁症和其他神经认知障碍，并伴有 1 型血管紧张素 II 受体、脑源性神经营养因子、GABA B 型受体亚基 2 (GABBR2)、GABRA3、GABRA5、 GABRB1、甘氨酸受体 β、谷氨酸离子型受体 N-甲基-D-天冬氨酸受体 (NMDA) 型亚基 1、谷氨酸离子型受体 NMDA 型亚基 2D、5-羟色胺受体 1D、干扰素 β 1 和核受体亚家族 3 C 组成员1为最高差异表达基因。对脑胶质细胞、神经元和 ADT 患者的验证研究证明了这些基因与认知能力下降之间的关联。我们的研究结果强调 LGIC 作为 ADT 介导的认知衰退的潜在生物标志物。这些生物标志物的进一步验证可能会导致未来的实际临床应用。