Factors Promoting Human Papillomavirus Mediated Cervical Carcinogenesis

High-risk human papillomavirus (HPV) is the causative agent of cervical cancer. Integration of the HPV genome into the host genome is a key event in cervical carcinogenesis, with oxidative stress (OS) likely playing a major role in promoting DNA damage, and subsequently, integration. In our current study, we demonstrated a chain of events leading from the induction of OS, to DNA damage, and then to viral integration. Induction of OS by either virus-mediated factors, such as expression of E6*, a splice variant of the E6 oncogene, or by exogenous factors led to DNA damage in normal oral keratinocytes and in cervical keratinocytes containing episomal HPV16. We found that OS increased the integration rate for both foreign DNA and HPV, while antioxidants reduced the integration frequency. We also demonstrated a significant variability in ROS levels in patient-derived cervical specimens, which may reflect differences in susceptibility to cervical cancer between women.