In summary, our results provide the first evidence for a functional involvement of HPV E6 in heparanase induction during head and neck tumourigenesis (most likely through p53-dependent mechanism) and may provide important avenue for future therapeutic exploration, relevant not only for HNSCC, but also for additional HPV-associated tumours, including cervical carcinoma (where heparanase overexpression is associated with aggressiveness and poor prognosis 44) and other types of lower genital tract neoplasms caused by HPV infection. Here, HPSE is linked to head and neck squamous cell carcinoma.