{“_”：“肾透明细胞癌预后、肿瘤微环境和药物敏感性的系统分析及其相关性”，“i”：[“UBE2D3”]}

摘要(中文译文)

铜代谢失调促进肾透明细胞癌(KIRC)的进展。本研究系统探讨了铜代谢相关基因在KIRC中的预后和治疗意义。利用癌症基因组图谱(TCGA)-KIRC转录组数据和临床记录(n=530)，我们分析了铜代谢相关基因的差异表达、生存相关性及临床意义。基于诊断/预后价值对 进行了优先级筛选。开展了功能富集、免疫浸润[通过估计RNA转录本相对亚群进行细胞鉴定(CIBERSORT)、肿瘤免疫估计资源(TIMER)、肿瘤免疫单细胞中心2(TISCH2)]、药物敏感性(oncoPredict)及分子对接分析。通过免疫组织化学(IHC)在9例临床KIRC标本中验证了UBE2D3蛋白表达。 表达在KIRC中较正常组织显著下调，且与晚期肿瘤分期/分级呈负相关(P<0.001)。 低表达预示较差的总生存期[风险比(HR)=0.67，P=0.002]，并可作为独立预后因素。 缺失与肿瘤免疫微环境改变相关，包括M1型巨噬细胞浸润减少和调节性T细胞增加。单细胞RNA测序证实 主要在单核细胞/巨噬细胞中表达。高甲基化和拷贝数变异显著影响 的失调。药物敏感性分析显示， -低表达肿瘤对长春新碱、博舒替尼和安巴腙更敏感[中位抑制浓度差异(IC diff.)P<0.01]，并得到有利的分子对接亲和力支持。 可能在KIRC中发挥抑癌作用，其在晚期阶段的下调及与生存改善的相关性支持了这一观点。相应地，其缺失似乎与晚期疾病、免疫抑制性肿瘤微环境(TME)和不良预后相关。其在调节免疫细胞动态和药物敏感性中的潜在作用使 成为KIRC预后判断和个体化治疗选择的有前景的生物标志物。

Abstract

Dysregulated copper metabolism contributes to kidney renal clear cell carcinoma (KIRC) progression. This study systematically investigated the prognostic and therapeutic implications of copper metabolism-related gene in KIRC. Utilizing The Cancer Genome Atlas (TCGA)-KIRC transcriptomic data and clinical records (n=530), we analyzed differential expression, survival correlation, and clinical significance of copper metabolism-related genes. was prioritized based on diagnostic/prognostic value. Functional enrichment, immune infiltration [Cell-Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT), Tumor Immune Estimation Resource (TIMER), Tumor Immune Single-cell Hub 2 (TISCH2)], drug sensitivity (oncoPredict), and molecular docking analyses were performed. UBE2D3 protein expression was validated via immunohistochemistry (IHC) in 9 clinical KIRC specimens. expression was significantly downregulated in KIRC versus normal tissue and inversely correlated with advanced tumor stage/grade (P<0.001). Low expression predicted poorer overall survival [hazard ratio (HR) =0.67, P=0.002] and served as an independent prognostic factor. loss associated with altered tumor immune microenvironment, including reduced M1 macrophage infiltration and increased regulatory T cells. Single-cell RNA sequencing confirmed predominant expression in monocytes/macrophages. Hypermethylation and copy number variation significantly influenced dysregulation. Drug sensitivity analysis revealed that -low tumors were more responsive to vincristine, bosutinib, and ambazone [median inhibitory concentration difference (IC diff.) P<0.01], supported by favorable molecular docking affinities. may function as a tumor suppressor in KIRC, as suggested by its downregulation in advanced stages and correlation with improved survival. Correspondingly, its loss appears to correlate with advanced disease, an immunosuppressive tumor microenvironment (TME), and unfavorable prognosis. This potential role in modulating immune cell dynamics and drug sensitivity positions as a promising biomarker for prognostication and personalized therapy selection in KIRC.

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