VDAC1在乳腺癌中的表达、临床预后及潜在作用机制的生物信息学分析

Bioinformatic Analysis of VDAC1 Expression, Clinical Prognosis and Potential Mechanisms in Breast Cancer

摘要: 目的：基于公共转录组数据库系统分析电压依赖性阴离子通道1 (VDAC1)在乳腺癌中的表达差异、与临床病理参数及患者预后的关联，挖掘其可能参与乳腺癌进展的相关分子通路，为乳腺癌代谢靶点与预后标志物筛选提供理论依据。方法：提取TCGA-BRCA队列1097例原发乳腺癌、114例正常乳腺组织转录组及完整临床随访数据，联合GEPIA2、UALCAN数据库验证VDAC1表达分布；分层分析VDAC1表达与患者年龄、绝经状态、PAM50分子亚型、TNBC精细亚型、TNM分期、腋窝淋巴结转移的相关性；构建ROC曲线评估VDAC1对乳腺良恶性病变的诊断效能；Kaplan-Meier法分析VDAC1表达与总生存期(OS)、无复发生存期(RFS)的关系，进一步基于PAM50分子亚型开展生存亚组分析；单、多因素Cox回归筛选乳腺癌独立预后危险因素；采用LinkedOmics筛选VDAC1共表达基因，开展GO/KEGG富集分析；Pearson相关分析VDAC1与线粒体氧化磷酸化关键基因的表达关联；STRING数据库构建VDAC1蛋白互作(PPI)网络。结果：VDAC1在乳腺癌组织中异常高表达，其表达水平与肿瘤侵袭进展、不良预后存在相关性，提示其可作为乳腺癌潜在诊断、预后分子标志物；其表达与线粒体氧化磷酸化与能量代谢重编程相关，提示其可能参与乳腺癌恶性进程，有望成为乳腺癌代谢靶向干预的潜在候选靶点。结论：VDAC1在乳腺癌中异常高表达，与肿瘤侵袭进展、不良预后存在相关性，提示其可作为乳腺癌潜在诊断、预后分子标志物；其表达与线粒体能量代谢重编程相关，提示其可能参与乳腺癌恶性进程，有望成为乳腺癌代谢靶向干预的潜在候选靶点。

Abstract: Objective: To systematically analyze the differential expression of voltage-dependent anion channel 1 (VDAC1), its correlations with clinicopathological parameters and patient prognosis in breast cancer based on public transcriptomic databases, to explore relevant molecular pathways potentially involved in breast cancer progression, and to provide theoretical evidence for screening metabolic therapeutic targets and prognostic biomarkers for breast cancer. Methods: Transcriptomic profiles and complete clinical follow-up data of 1097 primary breast cancer cases and 114 normal breast tissues were extracted from the TCGA-BRCA cohort. The expression pattern of VDAC1 was further validated using the GEPIA2 and UALCAN databases. Stratified analyses were performed to assess the correlations between VDAC1 expression and patient age, menopausal status, PAM50 molecular subtypes, refined TNBC subtypes, TNM stage, and axillary lymph node metastasis. Receiver-operating characteristic (ROC) curves were constructed to evaluate the diagnostic performance of VDAC1 for distinguishing benign and malignant breast lesions. The associations between VDAC1 expression and overall survival (OS) as well as relapse-free survival (RFS) were analyzed by the Kaplan-Meier method, and subgroup survival analyses were further conducted according to PAM50 molecular subtypes. Univariate and multivariate Cox regression analyses were applied to identify independent prognostic risk factors for breast cancer. LinkedOmics was used to screen VDAC1 co-expressed genes for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Pearson correlation analysis was used to evaluate expression correlations between VDAC1 and key genes involved in mitochondrial oxidative phosphorylation. The VDAC1 protein-protein interaction (PPI) network was constructed via the STRING database. Results: VDAC1 was aberrantly overexpressed in breast cancer tissues. Its expression level was correlated with tumor invasion-progression and unfavorable patient prognosis, suggesting that VDAC1 may serve as a potential diagnostic and prognostic biomarker for breast cancer. VDAC1 expression was correlated with mitochondrial oxidative phosphorylation and energy metabolic reprogramming, implying that it may participate in the malignant progression of breast cancer and could be a potential candidate target for metabolic-targeted intervention in breast cancer. Conclusion: VDAC1 is aberrantly overexpressed in breast cancer and its expression correlates with tumor invasion-progression and poor prognosis, which suggests its potential value as a diagnostic and prognostic biomarker for breast cancer. Its expression is associated with mitochondrial energy metabolic reprogramming, indicating that it may be involved in breast cancer malignant progression and represents a potential candidate target for metabolic-targeted therapy of breast cancer.