ZNF883在胃癌中的表达及预后意义：基于 生物信息学分析与WB验证

Expression and Prognostic Significance of ZNF883 in Gastric Cancer: A Bioinformatics Analysis and WB Validation

摘要: 目的：探讨锌指蛋白883 (ZNF883)在胃癌中的表达特征及其与患者预后的相关性，表达上调的分子诱因及预后价值，解析其参与胃癌发生发展的潜在信号通路，评估其作为胃癌诊断、预后标志物及潜在治疗靶点的应用前景。方法：基于TCGA数据库的胃癌(STAD)转录组数据，利用Ualcan、GEPIA3、cBioPortal等生物信息学数据库分析ZNF883在胃癌与癌旁组织中的表达差异，开展基因集富集分析(GSEA)并构建共表达网络预测下游信号通路；利用cBioPortal分析ZNF883拷贝数变异、DNA甲基化等基因组与表观遗传改变，阐明其表达上调机制。并评估其与患者总体生存期(OS)及无病生存期(DFS)的关系。同时，通过蛋白免疫印记(Western Blotting, WB)实验检测13对临床胃癌及配对癌旁组织中ZNF883的蛋白表达水平。结果：生物信息学分析显示，ZNF883在胃癌组织中的mRNA表达水平显著高于癌旁正常组织(P < 0.05)。基因组及表观遗传分析提示，ZNF883表达上调主要与DNA低甲基化、局部拷贝数扩增密切相关。GSEA及共表达网络分析显示，ZNF883主要富集于细胞周期、上皮间质转化(EMT)、细胞凋亡抑制、PI3K/Akt、Wnt/β-catenin等经典促癌信号通路。生存分析表明，ZNF883高表达组患者的OS和DFS均显著短于低表达组(P < 0.05)，HR > 1，提示其高表达是胃癌患者预后不良的危险因素。WB实验结果进一步证实，ZNF883蛋白在胃癌组织中呈显著高表达(P < 0.05)。结论：ZNF883因表观遗传及基因组异常出现表达上调，其高表达与胃癌患者不良预后高度相关，可能参与细胞周期紊乱、EMT、凋亡抵抗等恶性生物学过程。该基因不仅可作为胃癌诊断与预后评估的新型生物标志物，还有望成为胃癌靶向治疗新靶点，其表达水平或可用于预测化疗、靶向药物疗效。

Abstract: Objective: To investigate the expression characteristics of zinc finger protein 883 (ZNF883) in gastric cancer and its correlation with patient prognosis, the molecular inducers of its upregulated expression and prognostic value, elucidate the potential signaling pathways through which it participates in the initiation and progression of gastric cancer, and evaluate its application prospect as a diagnostic and prognostic biomarker as well as a potential therapeutic target for gastric cancer. Methods: Based on stomach adenocarcinoma (STAD) transcriptomic data from the TCGA database, bioinformatics databases including Ualcan, GEPIA3 and cBioPortal were used to analyze the differential expression of ZNF883 between gastric cancer tissues and adjacent non-tumor tissues. Gene set enrichment analysis (GSEA) was performed, and a co-expression network was constructed to predict downstream signaling pathways. The genomic and epigenetic alterations of ZNF883 such as copy number variation and DNA methylation were analyzed via cBioPortal to clarify the mechanism underlying its upregulated expression, and its associations with patients’ overall survival (OS) and disease-free survival (DFS) were assessed. Meanwhile, Western Blotting (WB) assay was applied to detect the protein expression levels of ZNF883 in 13 paired clinical gastric cancer tissues and matched adjacent non-tumor tissues. Results: Bioinformatics analyses revealed that the mRNA expression level of ZNF883 was significantly higher in gastric cancer tissues than in adjacent normal tissues (P < 0.05). Genomic and epigenetic analyses indicated that the upregulation of ZNF883 was closely associated with DNA hypomethylation and regional copy number amplification. GSEA and co-expression network analyses demonstrated that ZNF883 was mainly enriched in classic oncogenic signaling pathways including cell cycle, epithelial-mesenchymal transition (EMT), inhibition of apoptosis, PI3K/Akt and Wnt/β-catenin pathways. Survival analysis showed that patients with high ZNF883 expression exhibited markedly shorter OS and DFS compared with those with low ZNF883 expression (P < 0.05) with HR > 1, suggesting that its high expression serves as a risk factor for poor prognosis in gastric cancer patients. The results of WB assay further verified that ZNF883 protein was significantly overexpressed in gastric cancer tissues (P < 0.05). Conclusion: ZNF883 is upregulated due to epigenetic and genomic abnormalities, and its high expression is strongly correlated with unfavorable prognosis of gastric cancer patients. It may be involved in malignant biological processes such as cell cycle disorder, EMT and apoptosis resistance. This gene can act as a novel biomarker for the diagnosis and prognostic evaluation of gastric cancer, and is expected to become a new target for targeted therapy of gastric cancer. Its expression level may also be used to predict the efficacy of chemotherapy and targeted drugs.