Using high throughput technologies, our laboratory has identified the gene signatures and protein networks, which significantly affect HNSCC malignant phenotypes, including TP53/p63/p73 family members, IL-1/TNF-β/NF-κB, PI3K/AKT/mTOR, IL-6/IL-6R/JAK/STAT3, EGFR/MAPK/AP1, HGF/cMET/EGR1, and TGFβ/TGFβR/TAK1/SMAD pathways. This evidence concerns the gene PIK3CA and head and neck squamous cell carcinoma.