FOXM1 Upregulates CEP55 in a PI3K/Akt-Dependent Manner to Promote Oral Squamous Cell Carcinoma Metastasis

Background: Oral squamous cell carcinoma (OSCC) is characterized by high aggressiveness and poor prognosis due to frequent metastasis. Forkhead box M1 (FOXM1) acts as a potent oncogene in various cancers; however, the downstream molecular mechanisms by which FOXM1 drives OSCC metastasis remain unclear. This study aimed to investigate the regulatory relationship between FOXM1 and Centrosomal protein 55 (CEP55), and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in OSCC progression. Methods: The clinical relevance of FOXM1 and CEP55 was first validated using RNA sequencing (RNA-seq) data from the Cancer Genome Atlas Head and Neck Squamous Cell Carcinoma (TCGA-HNSC) dataset. For gene regulation analysis, FOXM1 and CEP55 expression in OSCC cell lines (CAL27 and SCC-9) was manipulated using small interfering RNAs (siRNAs) or overexpression plasmids, and regulatory relationships were assessed by quantitative reverse transcription PCR (qRT-PCR) and Western blotting. For functional assays, cell migration and invasion were assessed using wound healing and Transwell assays under serum-free conditions. Mechanistic studies examined the involvement of the PI3K/Akt pathway using SC79 as a specific Akt activator, and rescue experiments were performed by co-transfection of the CEP55 overexpression plasmid. Results: Bioinformatics analysis revealed that both FOXM1 and CEP55 were significantly overexpressed in head and neck squamous cell carcinoma (HNSCC) tumor tissues compared to normal tissues (p < 2 × 10-16 for both), with a strong positive correlation between their expression levels (Spearman r = 0.754). We found that FOXM1 positively regulated CEP55 expression at both mRNA and protein levels (p < 0.001). Functionally, FOXM1 knockdown significantly inhibited, whereas FOXM1 overexpression promoted, the migration and invasion capabilities of OSCC cells (p < 0.001). Mechanistically, FOXM1 depletion suppressed Akt phosphorylation (p < 0.001). Notably, pharmacological activation of Akt by SC79 successfully restored CEP55 protein abundance in FOXM1-silenced cells (p < 0.001), suggesting that the PI3K/Akt pathway is critical for maintaining CEP55 levels downstream of FOXM1. Furthermore, rescue experiments demonstrated that re-introduction of CEP55 reversed the migration and invasion defects induced by FOXM1 knockdown (p < 0.001). Conclusion: Our findings indicate that FOXM1 promotes migration and invasion in OSCC cell lines by upregulating CEP55 through the PI3K/Akt signaling axis. This study highlights the FOXM1/PI3K/Akt/CEP55 network as a potential therapeutic target worthy of further in vivo and clinical investigation in OSCC.