Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses

Human papillomaviruses (HPV) are the causative agents of cervical cancer and have been shown to increase expression of pro-angiogenic factors from infected cells. Many angiogenic factors are regulated by hypoxia inducible factor 1alpha (HIF-1alpha). We investigated whether HPV31 affects the levels of HIF-1alpha under normal and hypoxic conditions. Our studies indicate that cells containing complete HPV31 genomes showed enhanced levels of HIF-1alpha upon treatment with the hypoxia mimic DFO, which resulted from protein stabilization and led to increased expression of some but not all HIF-1alpha target genes. Both HPV E6 and E7 were able independently to enhance induction of HIF-1alpha upon DFO treatment. Enhancement of HIF-1alpha stability was not restricted to high-risk HPV types, as HPV11, a low risk HPV type, mediated a similar effect. These findings shed light on mechanisms by which HPV contributes to angiogenesis both in benign cervical lesions and in cervical cancers.