Integrated Network Analysis Reveals a Directly Regulatory Network of FOXM1 Associated With the Cell Cycle in Lung Adenocarcinoma

Lung adenocarcinoma (LUAD) has emerged as both the most frequently diagnosed malignancy and the predominant contributor to cancer-related mortality worldwide. Current clinical evidence indicates that a significant proportion of LUAD cases exhibit tumor cells characterized by accelerated proliferative activity, which contributes to the aggressive biological behavior. Six microarray data sets were retrieved from the Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) were identified using the robust rank aggregation (RRA) method. The mRNA and protein levels of selected genes were subsequently validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB). Short interfering RNA (siRNA)-mediated knockdown combined with EdU incorporation assays was employed to assess proliferation in LUAD cell lines. Chromatin immunoprecipitation (ChIP) assays confirmed that FOXM1 directly regulates the transcription of its target genes. A total of 291 DEGs (133 up-regulated and 158 down-regulated) were identified. Up-regulated genes were significantly enriched in cell-cycle pathways. The FOXM1 exhibited the strongest correlation with these cell-cycle genes and was shown by ChIP-seq to bind to the promoters of 49 of them. TOP2A , MELK , CENPF , NEK2 , and KIF20A are the top 5 genes for further analysis in the The Cancer Genome Atlas (TCGA) database. These 5 genes are all highly expressed and show a worse prognosis in LUAD. Cell experiments showed that FOXM1 knockdown only inhibited the expression of CENPF and NEK2. Knocking down either FOXM1 or CENPF can inhibit the proliferation of LUAD cells. Overexpression of FOXM1 promoted CENPF expression and the proliferation of lung cancer cells. The predicted regulatory network of FOXM1 shows significant discrepancies with experimental validation data. Therefore, FOXM1’s regulatory role in the cell cycle requires further experimental verification.