The Biological and Prognostic Implications of the Nicotinic Acetylcholine Receptor α3, α5, and α7 Subunits in Oral Squamous Cell Carcinoma.

BACKGROUND

The divergent loop structures of nicotinic acetylcholine receptor (nAChR) α3, α5, and α7 subunits (encoded by CHRNA3, CHRNA5, and CHRNA7) are involved in kinase phosphorylation and signal transduction, potentially affecting oral squamous cell carcinoma (OSCC), the most common head and neck cancer (HNC). However, their specific roles in OSCC remain unclear.

METHODS

We integrated analyses of SCC-4 tongue cancer cells with CHRNA overexpression, immunohistochemistry of OSCC pathological specimens, and data from the cancer genome atlas (TCGA), DepMap, and Puram 2017 to assess CHRNA3, CHRNA5, and CHRNA7 in OSCC/HNC.

RESULTS

In OSCC, CHRNA3, CHRNA5, and CHRNA7 expression interacted with epithelial-mesenchymal transition (EMT) markers and correlated with invasive patterns. CHRNA3 reduced epithelial and enhanced mesenchymal traits, supporting EMT. CHRNA5 further promoted mesenchymal features, was linked to disseminated tumor patterns, and predicted poor prognosis. CHRNA7 enhanced both epithelial and mesenchymal markers, maintaining a hybrid EMT state. In HNC, bioinformatic analyses revealed that CHRNA3 preserved ion channel activity, CHRNA5 promoted DNA replication, reduced adhesion, suppressed antigen presentation, and induced hypomethylation and miRNA overexpression, while CHRNA7 promoted differentiation with variable effects on adhesion and antigen presentation. In DepMap HNC cell lines, high CHRNA3/CHRNA5 and low CHRNA7 expression were associated with resistance to most inhibitors. Epidermal growth factor receptor (EGFR) inhibitors were effective in CHRNA3/CHRNA7-high HNC, whereas cyclin-dependent kinase (CDK) inhibitors were effective in CHRNA5-high HNC.

CONCLUSION

Differential expression of CHRNA3, CHRNA5, and CHRNA7 indicates different EMT states in OSCC/HNC, influencing proliferation, differentiation, cell adhesion, immune reactions, and treatment efficacy, and warrants further experimental validation.