Consistently, upregulation of the metastasized tumor formation was observed in systemic Igfbp3 knockout (KO) mice, wherein tongue tumors were induced by 4-nitroquinoline-1-oxide (4-NQO) [27], and wild-type mice in which xenograft tumors were established by orthotopic or subcutaneous injection of human HNSCC or NSCLC cells with knocked down IGFBP-3 expression. This evidence concerns the gene IGFBP3 and head and neck squamous cell carcinoma.