Here, we addressed the role of signaling pathways involved in HPV16 E7-mediated PIR/NF-κB activation and oral cell migration, finding that HPV16 E7 promotes the activation of the EGFR/PI3K/AKT/NRF2 signaling pathway, in turn stimulating PIR-mediated NF-κB activation in oral cancer cells. This evidence concerns the gene PIR and lip and oral cavity carcinoma.