EGFR Signaling As the Nexus for HPV Oncogene Regulation

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ABSTRACT A subset of human papillomaviruses (HPVs) cause nearly 5% of the world’s cancers. The HPVs are small non-enveloped, double-stranded DNA viruses that have a tropism for squamous epithelium. HPVs are completely dependent on normal epithelial differentiation for completion of their replicative cycles. HPVs infect basal epithelial cells where they establish extra-chromosomal replication of their genomes. As infected basal cells divide and daughter cells move to the upper cell layers, the expression of the early viral E6 and E7 proteins promote proliferation of the suprabasal epithelial layers. This results in a phenotype of epithelial dysplasia and expansion of HPV infected cells. Broadly, two outcomes become possible. One outcome is a productive infection. Herein, cellular differentiation ensues, viral E6 and E7 gene expression is suppressed, and HPV late gene expression is activated to complete the virus life cycle and yield progeny virions. In the second outcome, the maintained (deregulated) expression of the E6 and E7 proteins continues to promote proliferation and inhibit tissue differentiation. However, little is known about how HPV oncogene expression is regulated during the process of epithelial tissue differentiation or how regulation is lost during carcinogenesis. To study HPV oncogene regulation, we are using cell lines that grow as neoplastic tissues able to recapitulate the entire HPV life cycle in organotypic epithelial tissue cultures. Our data indicate that epidermal growth factor receptor (EGFR) signaling and contact inhibition influence HPV oncogene expression. We find that HPV oncogene expression is transcriptionally down-regulated concomitant with suppression of EGFR signaling as cells become increasingly confluent. Furthermore, EGF stimulation of confluent cells restores E6 and E7 expression, but this can be hindered with inhibitors of EGFR, MEK, or ERK. In this proposal I will define the effectors of EGFR that regulate E6/E7 transcription and will determine the mechanism by which EGFR signaling is influenced by epithelial interactions to effect viral oncogene transcription.