Lung cancer is the leading cause of cancer-related deaths worldwide, and despite recent advances in targeted therapies and immunotherapies, the clinical benefit remains limited. Therefore, there is an urgent need to further investigate the molecular mechanisms underlying lung cancer. The aim of this study was to investigate the expression and function of NPM3 in the tumor microenvironment of lung adenocarcinoma (LUAD). We utilized bioinformatics tools and databases, including UALCAN, GEPIA2, HPA, and Sangerbox, to analyze NPM3 expression in LUAD samples and its association with prognosis and mutational landscape. NPM3 expression in various cell types was assessed at the single cell level using the TISCH database. We also used algorithms such as TIMER and EPIC to explore the crosstalk between NPM3 expression and immune features. KEGG enrichment analysis was performed to identify potential signaling pathways of NPM3. Finally, we employed siRNA knockdown strategy to investigate the effect of NPM3 on LUAD cell proliferation and migration in vitro. NPM3 was significantly upregulated in LUAD tissues and was strongly associated with poor prognosis and TP53 gene mutations. Single-cell sequencing analysis revealed that NPM3 was expressed in immune cells (dendritic cells and monocytes/macrophages) in the tumor microenvironment. Moreover, NPM3 expression was negatively associated with immune B cell and CD4 T cell infiltration, as well as with several immune-related genes (including CCL22, CXCR2, CX3CR1, CCR6, HLA-DOA, HLA-DQA2). KEGG enrichment analysis indicated that NPM3 expression was associated with cell cycle, CAMs, and NSCLC pathway genes. Finally, in vitro experiments showed that NPM3 knockdown inhibited LUAD cell proliferation and migration in NCI-H1299 and SPC-A1 cells, and suppressed the expression of CCNA2 and MAD2L1. Elevated NPM3 expression predicts poor clinical outcome and an immunosuppressive microenvironment in LUAD tissues. NPM3 promotes LUAD progression by promoting cell proliferation and migration, and targeting NPM3 may represent a novel therapeutic strategy for LUAD.

中文翻译：

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NPM3 作为一种新型致癌因子和不良预后标志物有助于肺腺癌的细胞增殖和迁移

肺癌是全世界癌症相关死亡的主要原因，尽管最近在靶向治疗和免疫治疗方面取得了进展，但临床益处仍然有限。因此，迫切需要进一步研究肺癌的分子机制。本研究旨在探讨 NPM3 在肺腺癌 (LUAD) 肿瘤微环境中的表达和功能。我们利用生物信息学工具和数据库，包括 UALCAN、GEPIA2、HPA 和 Sangerbox，分析 LUAD 样本中的 NPM3 表达及其与预后和突变景观的关联。使用 TISCH 数据库在单细胞水平评估各种细胞类型中的 NPM3 表达。我们还使用了 TIMER 和 EPIC 等算法来探索 NPM3 表达与免疫功能之间的串扰。进行 KEGG 富集分析以确定 NPM3 的潜在信号通路。最后，我们采用 siRNA 敲低策略研究 NPM3 对 LUAD 细胞体外增殖和迁移的影响。NPM3 在 LUAD 组织中显着上调，并且与不良预后和 TP53 基因突变密切相关。单细胞测序分析表明，NPM3 在肿瘤微环境中的免疫细胞（树突状细胞和单核细胞/巨噬细胞）中表达。此外，NPM3 表达与免疫 B 细胞和 CD4 T 细胞浸润以及几种免疫相关基因（包括 CCL22、CXCR2、CX3CR1、CCR6、HLA-DOA、HLA-DQA2）呈负相关。KEGG 富集分析表明 NPM3 表达与细胞周期、CAM 和 NSCLC 通路基因相关。最后，体外实验表明，NPM3 敲低抑制了 NCI-H1299 和 SPC-A1 细胞中 LUAD 细胞的增殖和迁移，并抑制了 CCNA2 和 MAD2L1 的表达。升高的 NPM3 表达预示着临床结果不佳和 LUAD 组织中的免疫抑制微环境。NPM3 通过促进细胞增殖和迁移促进 LUAD 进展，靶向 NPM3 可能代表 LUAD 的新治疗策略。