Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:3312.

A keratinocyte life cycle model identifies novel host genome regulation by human papillomavirus 16 relevant to HPV positive head and neck cancer

Michael R. Evans, Claire D. James, Oonagh Loughran, Tara J. Nulton, Xu Wang, Molly L. Bristol, Brad Windle and Iain M. Morgan _

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Oncotarget. 2017; 8:81892-81909. https://doi.org/10.18632/oncotarget.18328

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Abstract

Michael R. Evans1, Claire D. James1, Oonagh Loughran1, Tara J. Nulton1, Xu Wang1, Molly L. Bristol1, Brad Windle1,2 and Iain M. Morgan1,2

1 Department of Oral and Craniofacial Molecular Biology, VCU Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Richmond, VA, USA

2 VCU Massey Cancer Center, Richmond, VA, USA

Correspondence to:

Iain M. Morgan, email:

Keywords: head and neck cancer, human papillomavirus, life-cycle, the cancer genome atlas, keratinocytes

Received: May 07, 2017 Accepted: May 17, 2017 Published: June 01, 2017

Abstract

Many aspects of the HPV life cycle have been characterized in cervical cell lines (W12, CIN612) and in HPV immortalized primary foreskin keratinocytes. There is now an epidemic of HPV positive oropharyngeal cancers (HPV16 is responsible for 80-90% of these); therefore increased understanding of the HPV16 life cycle in keratinocytes is a priority. Using TERT immortalized “normal” foreskin keratinocytes (N/Tert-1) we generated clonal cell lines maintaining the HPV16 genome as an episome, N/Tert-1+HPV16. Organotypic raft cultures demonstrated appropriate expression of differentiation markers, E1^E4 and E2 expression along with amplification of the viral genome in the upper layers of the epithelium. Using this unique system RNA-seq analysis revealed extensive gene regulation of the host genome by HPV16; many of the changes have not been observed for HPV16 before. The RNA-seq data was validated on a key set of anti-viral innate immune response genes repressed by HPV16 in N/Tert-1+HPV16. We show that the behavior of these N/Tert-1+HPV16 lines is similar to HPV16 immortalized human tonsil keratinocytes with regards innate gene regulation. Finally, using The Cancer Genome Atlas (TCGA) data we examined gene expression patterns from HPV positive and negative head and neck cancers and demonstrate this innate immune gene signature set is also downregulated in HPV positive cancers versus negative. Our system provides a model for understanding HPV16 transcriptional regulation of keratinocytes that is directly relevant to HPV positive head and neck cancer.


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