Abstract
Oral squamous cell carcinoma (OSCC) is a highly prevalent head and neck malignancy with a poor prognosis, often exhibiting resistance to conventional therapies. This highlights an urgent need for reliable biomarkers to facilitate early detection and effective management of recurrent or metastatic cases. Leveraging multi-omics analysis, we identified the HOX gene family as significantly overexpressed and closely associated with OSCC progression. Among these, HOXC9 was prioritized as a key regulator using machine learning algorithms. Mechanistic investigations revealed a strong correlation between HOXC9 expression and DNA hypomethylation at the CDX1 motif, which play a crucial role in regulating MMP13 expression. Single-cell RNA sequencing further elucidated the role of HOXC9 in driving OSCC malignant transformation. Clinical evidence demonstrates that HOXC9 promotes OSCC invasion and metastasis through the ITGA6/PI3K/Akt/MMP13 signaling axis. Additionally, HOXC9 expression appears to be modulated by miR-196, presenting a potential target for therapeutic intervention in OSCC.