Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
Science Island Branch, Graduate School of University of Science and Technology of China, Hefei 230026, China.
Molecules. 2023 Jan 22;28(3):1103. doi: 10.3390/molecules28031103.
The oncogenic role of Ladinin-1 (LAD1), an anchoring filament protein, is largely unknown. In this study, we conducted a series of studies on the oncogenic role of LAD1 in lung adenocarcinoma (LUAD). Firstly, we analyzed the aberrant expression of LAD1 in LUAD and its correlation with patient survival, tumor immune infiltration, and the activation of cancer signaling pathways. Furthermore, the relationship between LAD1 expression and K-Ras and EGF signaling activation, tumor cell proliferation, migration, and colony formation was studied by gene knockout/knockout methods. We found that LAD1 was frequently overexpressed in LUAD, and high LAD1 expression predicts a poor prognosis. LAD1 exhibits promoter hypomethylation in LUAD, which may contribute to its mRNA upregulation. Single-sample gene set enrichment analysis (ssGSEA) showed that acquired immunity was negatively correlated with LAD1 expression, which was verified by the downregulated GO terms of "Immunoglobulin receptor binding" and "Immunoglobulin complex circulating" in the LAD1 high-expression group through Gene Set Variation Analysis (GSVA). Notably, the Ras-dependent signature was the most activated signaling in the LAD1 high-expression group, and the phosphorylation of downstream effectors, such as ERK and c-jun, was strongly inhibited by LAD1 deficiency. Moreover, we demonstrated that LAD1 depletion significantly inhibited the proliferation, migration, and cell-cycle progression of LUAD cells and promoted sensitivity to Gefitinib, K-Ras inhibitor, and paclitaxel treatments. We also confirmed that LAD1 deficiency remarkably retarded tumor growth in the xenograft model. Conclusively, LAD1 is a critical prognostic biomarker for LUAD and has potential as an intervention target.
锚定丝蛋白 Ladinin-1（LAD1）的致癌作用在很大程度上尚不清楚。在本研究中，我们对 LAD1 在肺腺癌（LUAD）中的致癌作用进行了一系列研究。首先，我们分析了 LAD1 在 LUAD 中的异常表达及其与患者生存、肿瘤免疫浸润和癌症信号通路激活的相关性。此外，我们还通过基因敲除/敲除方法研究了 LAD1 表达与 K-Ras 和 EGF 信号激活、肿瘤细胞增殖、迁移和集落形成的关系。我们发现 LAD1 在 LUAD 中频繁过表达，且高 LAD1 表达预示着不良预后。LAD1 在 LUAD 中表现出启动子低甲基化，这可能导致其 mRNA 上调。单样本基因集富集分析（ssGSEA）显示，获得性免疫与 LAD1 表达呈负相关，通过基因集变异分析（GSVA）在 LAD1 高表达组中下调了“免疫球蛋白受体结合”和“免疫球蛋白复合物循环”的 GO 术语，验证了这一结果。值得注意的是，LAD1 高表达组中最活跃的信号是 Ras 依赖性信号，LAD1 缺失强烈抑制下游效应物如 ERK 和 c-jun 的磷酸化。此外，我们证明 LAD1 耗竭可显著抑制 LUAD 细胞的增殖、迁移和细胞周期进程，并增强对 Gefitinib、K-Ras 抑制剂和紫杉醇的敏感性。我们还证实 LAD1 缺失可显著抑制异种移植模型中的肿瘤生长。综上所述，LAD1 是 LUAD 的一个关键预后生物标志物，具有作为干预靶点的潜力。
