Asian-American variant of human papillomavirus 16 E6 promotes the Warburg effect and hypoxia-inducible factor 1 signalling under hypoxia / by Sean Cuninghame.

Abstract

Infection with high-risk human papillomavirus (HPV) is responsible for nearly all cases of cervical cancer, as well as a significant fraction of other ano-genital and head and neck cancers. Specifically, HPV type 16 (HPV 16) causes the majority of cervical cancers attributed to HPV infection. Intratypic variation occurs within the HPV16 genome such that naturally occurring variants have been described that display variable risks in promoting cervical cancer. In particular, the Asian-American (AA) variant of HPV16 has been found to be a greater risk factor for the development and earlier onset of invasive cervical cancer than the European Prototype (EP). Keratinocytes transduced with the AA variant were previously shown to have increased levels of glycolytic enzymes, implying AAE6 may enhance the Warburg effect - the tendency of cancer cells to take up higher levels of glucose and metabolize it to lactate. Therefore, glucose consumption and lactate production were assessed in the context of these variants and AAE6 was found to enhance the Warburg effect. To elucidate the mechanism behind this shift in metabolism, the hypoxia-inducible factor 1 (HIF-1) pathway was investigated. HIF-1 is a heterodimeric transcription factor made up of [alpha symbol] and [beta symbol] subunits, and enhances the transcription of genes involved in the Warburg effect. Even under normoxic conditions, HIF-1 a is detectable in AAE6 cells, and its levels are higher in the nucleus than in EPE6 cells. A HIF-1-specific reporter assay found HIF-1 activity to be greater in AAE6 in comparison to EPE6 under hypoxia, a typical hallmark of the tumour microenvironment. Gene expression analysis found that the HIF-1 targets GLUTl and VEGF-A are induced to a greater degree in AAE6 cells exposed to hypoxia. Future studies can elucidate the functionality of HIF-1 in AAE6’s enhanced invasive potential via RNA-interference.