CDKN2A and matrix metalloproteinases: key regulators of cellular senescence in squamous cell carcinoma.

Objectives: This study aimed to investigate the role of cellular senescence in the progression of squamous cell carcinoma (SCC) and to identify key senescence-associated biomarkers and pathways that contribute to tumor aggressiveness.

Methods: RNA sequencing data from SCC and normal skin tissues (GSE191334) were analyzed using the DESeq2 package to identify differentially expressed genes (DEGs). Upregulated DEGs were cross-referenced with the CellAge database to identify senescence-related biomarkers. Functional enrichment analyses were conducted using EnrichR, GeneCodis4, and KEGG databases. Protein-protein interaction networks were mapped using STRING, and mutational profiling of CDKN2A was performed via the G2P portal and UCSC Xena.

Results: A total of 1,448 genes were upregulated and 1,700 downregulated in SCC. Among these, 38 upregulated genes were associated with cellular senescence. Notably, CDKN2A was prominently expressed, suggesting a stress-induced senescence response. CDKN2A, along with MMP3 and MMP12, formed central hubs within interaction networks, implicating them in extracellular matrix remodeling and tumor invasiveness. Enrichment analyses highlighted activation of epithelial-to-mesenchymal transition (EMT), inflammatory signaling, and senescence-associated secretory phenotype (SASP). Immune-modulatory genes such as ULBP2 and IL6 were also elevated. Mutation analysis revealed alterations in the CDKN2A-encoded p16^INK4a^, potentially disrupting its tumor-suppressive functions.

Conclusions: Cellular senescence in SCC exhibits a dual role - initially tumor-suppressive, later promoting invasion and metastasis. Key biomarkers such as CDKN2A and MMPs may serve as therapeutic targets. These findings lay the groundwork for future translational research to improve SCC diagnosis and treatment.