School of Medical Technology and Engineering, Henan University of Science and Technology, Luoyang, China.
Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China.
Medicine (Baltimore). 2024 Feb 2;103(5):e37041. doi: 10.1097/MD.0000000000037041.
Lung adenocarcinoma (LUAD) is a common malignant tumor. Identification of biomarkers and understanding their potential functions will facilitate the treatment and diagnosis in LUAD patients. The yellow module (cor = 0.31, P = 2e-6) was selected as the core module based on weighted gene co-expression network analysis (WGCNA) by integrating RNA-seq data and tumor stage. Two upregulated genes (PLAU and GREM1) in yellow module were identified to be biomarkers. Kaplan-Meier curve analysis displayed that high expression levels of them had a poor overall survival (OS). And, their high expression levels revealed higher tumor stage and relapse possibility in LUAD patients, and could be a prognostic parameter. Both biomarkers showed similar immune cell expression profiles in low- and high-expression groups. Strongly positive correlation between both biomarkers and biomarkers of tumor-infiltrating lymphocytes were also clarified in TCGA-LUAD cohort. Importantly, single gene GSEA showed that transcriptional mis-regulation in cancer and microRNAs in cancer were enriched in LUAD patients. Therefore, a miRNA-mRNA-transcription factors (TFs) co-expression regulatory networks was constructed for each biomarker, various miRNAs and TFs were related to PLAU and GREM1. Among which, 6 downstream TFs were overlapped genes for both biomarkers. Notably, 2 of these TFs (FOXF1 and TFAP2A) exhibited significantly abnormal expression levels. Among which, FOXF1 was downregulated and TFAP2A was upregulated in TCGA-LUAD cohort. Both TFs showed a significantly positive correlation with the expression level of PLAU. In conclusion, we identified 2 biomarkers related to immune response and achieved a good accuracy in predicting OS in patients with LUAD.
肺腺癌（LUAD）是一种常见的恶性肿瘤。鉴定生物标志物并了解其潜在功能将有助于 LUAD 患者的治疗和诊断。基于 RNA-seq 数据和肿瘤分期，通过整合加权基因共表达网络分析（WGCNA），选择黄色模块（cor=0.31，P=2e-6）作为核心模块。鉴定出黄色模块中两个上调基因（PLAU 和 GREM1）为生物标志物。Kaplan-Meier 曲线分析显示，其高表达水平与总生存期（OS）较差相关。并且，它们的高表达水平表明 LUAD 患者的肿瘤分期较高且复发可能性较高，并且可以作为预后参数。两个生物标志物在低表达和高表达组中的免疫细胞表达谱相似。在 TCGA-LUAD 队列中还阐明了两个生物标志物与肿瘤浸润淋巴细胞标志物之间的强正相关。重要的是，单个基因 GSEA 显示癌症转录失调和癌症中的 microRNAs 在 LUAD 患者中富集。因此，为每个生物标志物构建了 miRNA-mRNA-转录因子（TFs）共表达调控网络，多种 miRNA 和 TFs 与 PLAU 和 GREM1 相关。其中，有 6 个下游 TF 是两个生物标志物的重叠基因。值得注意的是，这两个 TF 中的 2 个（FOXF1 和 TFAP2A）表现出明显异常的表达水平。其中，FOXF1 在 TCGA-LUAD 队列中下调，而 TFAP2A 上调。这两个 TF 与 PLAU 的表达水平呈显著正相关。总之，我们鉴定了 2 个与免疫反应相关的生物标志物，在预测 LUAD 患者的 OS 方面取得了良好的准确性。
