CHAPTER 1
carcinomas (induced by a high-risk HPV infection) and the HPV-negative carcinomas (mostly induced by the traditional risk factors smoking and alcohol consumption). HPV-positive HNSCC
HPV-positive HNSCC are induced by infection with HPV. HPV is a heterogeneous family of over 100 different double-strained, small DNA viruses, of which at least 15 types are classified as ‘high risk’ based on their oncogenic potential. However, over 90% of all HPV-
associated HNSCC are caused by one viral type: HPV16 [26]. Its genome consists of nine genes: seven early genes (E1, E2, E3, E4, E5, E6 and E7) and two late genes (L1 and L2).
E2 regulates expression of E6 and E7. Integration of the HPV genome in the host cell DNA or a highly methylated binding site E2 binding site, leads to loss of E2 expression and
thereby deregulates expression of the oncoproteins E6 and E7. As a consequence, both
E6 and E7 are expressed disproportionally. E6 binds and inactivates the p53 protein, leading to substantial loss of p53 activity. p53 has an important role in response to DNA
damage by arresting cells in G1 or inducing apoptosis to allow host DNA to be repaired.
Due to E6 expression, the p53-mediated apoptotic pathway is inactivated, which makes
these cells susceptible to genomic instability. The E7 protein binds and inactivates the retinoblastoma (Rb) protein, causing the cell to enter S-phase, leading to cell-cycle disruption, proliferation, and malignant transformation [27]. Furthermore, viral oncoproteins also target and modulate the Notch, Wnt and P13K/AKT/mTOR pathways [28].
Figure 3. Proposal of an integrated model of molecular carcinogenesis for head and neck squamous cell carcinoma [2].
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