The impact of LncRNA-SOX2-OT/let-7c-3p/SKP2 Axis on head and neck squamous cell carcinoma progression: Insights from bioinformatics analysis and experimental validation.

ABSTRACT

BACKGROUND: LncRNA SRY-box transcription factor 2 overlapping transcript (SOX2-OT) is linked to multiple cancers, but its specific role and mechanism in head and neck squamous cell carcinoma (HNSCC) remain poorly understood. METHODS: We harnessed clinical data and HNSCC transcriptome profiles from UCSC Xena, TCGA, and GEO databases. Employing various algorithms, we assessed the correlation between SOX2-OT expression and the HNSCC immune microenvironment. Differential expression analysis identified immune-enriched miRNAs (DEmiRNAs) and mRNAs (DEmRNAs). Utilizing miRanda, miRWalk, and Cytoscape, we constructed a ceRNA network encompassing SOX2-OT, DEmiRNAs, and DEmRNAs. A Sankey diagram visualized pivotal SOX2-OT-miRNA-mRNA-pathways. Functional assays validated SOX2-OT silencing effects in HNSCC cells. Luciferase reporter assays verified SOX2-OT/let-7c-3p/SKP2 relationships. Additionally, a xenograft mouse model revealed SOX2-OT's impact on xenograft growth and lung metastasis. RESULTS: SOX2-OT expression demonstrated a predominantly positive correlation with B lineage and VTCN1, while manifesting a negative correlation with Neutrophil and CD47 in HNSCC tissues. We discerned a ceRNA network comprising 65 DEmiRNAs and 116 DEmRNAs, while a protein-protein interaction (PPI) network revealed 97 protein nodes among DEmRNAs. Notably, the Sankey diagram spotlighted six key DEmRNAs intricately linked to the SOX2-OT-regulated DEmiRNAs immune-related pathway. Experimental assays established that SOX2-OT silencing exerted inhibitory effects on cell proliferation, migration, tumor growth, and lung metastasis within HNSCC cells, both in vitro and in vivo. We identified let-7c-3p as a target miRNA of SOX2-OT and SKP2 as a target mRNA of let-7c-3p. CONCLUSIONS: Our study establishes the critical SOX2-OT/let-7c-3p/SKP2 axis as a pivotal regulator of HNSCC tumorigenesis and metastasis.