Title: Inhibition of EGFR Signal Transduction in Human Keratinocytes Infected with Oncogenic HPV Leads to a Decrease in Viral Transcript Levels and Genome Numbers
Authors: Anastacia M. Maldonado1 and Michelle A. Ozbun1
Affiliations: 1Department of Molecular Genetics and Microbiology, University of New Mexico
Abstract: Human Papillomaviruses (HPVs) are known to cause 99.9% of cervical cancers as well as subsets of anogenital and orophargeal cancers. Vaccination against the two most common oncogenic HPV types (HPV-16 and -18) has proven effective in decreasing the number of infected individuals. However, the prohibitively high cost of the vaccine and low uptake rate continue to limit its effectiveness. Therefore, continuing research on prophylactic and therapeutic interventions is needed. It has previously been shown that HPV early proteins regulate EGFR expression and recycling in infected cells. Although many epithelial cancers have increased EGFR expression there are conflicting data regarding EGFR expression levels in tissues collected from HPV infected lesions. Our lab has proposed that HPV infection establishes an intracellular positive feedback loop with the EGFR signaling pathway that does not require high levels of EGFR expression. This feedback loop results in increased EGFR signal transduction leading to enhanced viral transcription through modulation of cell survival and proliferation determinants. In this study, the effect of EGFR and MAPK inhibitors on viral transcription, genome maintenance, and cell viability was tested on cells containing oncogenic HPV genomes. Our results indicate that EGFR pathway inhibitors cause a down-regulation of viral early transcripts and genome copies in these cell types in vitro. In light of these results, we propose that topical use of an EGFR inhibitor may be useful in the treatment of HPV infected lesions in lieu of or concurrent with surgical removal of infected, abnormal tissue prior to viral integration.