Thus, co-immunoprecipitation of CTNNB1 and MDA-9/Syntenin, and alteration of CTNNB1 following MDA-9/Syntenin depletion or overexpression suggest for a MDA-9/Syntenin and CTNNB1 signaling axis in regulating HNSCC differentiation in concert with SPRR1B. The gene discussed is CTNNB1; the disease is head and neck squamous cell carcinoma.