Biomedical Sciences ETDs

Publication Date

7-1-2016

Abstract

Human papillomaviruses (HPVs) are the most common sexually transmitted infectious agents. They are responsible for >99% of all cervical cancers as well as subsets of other anogenital cancers. HPVs are also the causative agents of a growing number of head and neck cancers. As such, they present a significant health problem both in the U.S. and developing countries. Much is still unknown regarding the factors underlying progression from HPV infection to cancer or maintenance of viral oncoprotein expression following oncogenic transformation. Previous studies reported significant interplay between the epidermal growth factor (EGFR) pathway and HPV oncoproteins. HPV oncoproteins E5, E6, and E7 have been implicated in upregulation of EGFR signaling and expression. Additionally, downstream effectors of EGFR signaling were shown to upregulate HPV early gene expression. These reports led us to hypothesize that, in infected cells, HPV establishes a positive feedback loop with the EGFR pathway, wherein viral proteins upregulate EGFR signaling, which then leads to enhanced viral oncogene expression. We further postulated that interruption of this feedback loop, via inhibitors of the EGFR signaling pathway, would result in decreased viral oncoprotein levels and increased sensitivity to apoptotic stimuli. In a model of early, persistent infection, we found that EGFR signaling modulated HPV early gene expression, including upregulation of viral oncogene expression upon EGFR stimulation. We discovered that EGFR inhibition by cetuximab, a monoclonal antibody targeting EGFR, had antiviral effects including downregulation of HPV oncogene expression levels in this model. Furthermore, in cells harboring episomal viral genomes, inhibition of this pathway led to reduced viral genome burden and sensitization to apoptotic stimuli. Our study further reveals that EGFR/MEK inhibition can lead to downregulation of HPV oncogene expression in vivo, in subsets of HPV-positive xenografts, concomitant with delayed tumor growth. These results suggest a possible role for antiviral effects in the therapeutic outcomes observed following EGFR-inhibitor treatment of HPV-associated diseases in the clinic. Together, these data indicate that use of EGFR/MEK inhibitors may be beneficial in the treatment of HPV-associated diseases. Furthermore, the results of this study set the frame work to better understand the role of growth factor signaling in the HPV lifecycle.

Keywords

HPV, EGFR, growth factor receptor, human papillomavirus, cetuximab, cancer

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Hudson, Laurie

Second Committee Member

Chackerian, Bryce

Third Committee Member

Hathaway, Helen

Fourth Committee Member

Wilson, Bridget

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