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

Oncotarget
Michael R EvansIain M Morgan

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 oral keratinocytes is a priority. To date there have been limited reports characterizing the HPV16 life cycle in oral keratinocytes. Using TERT immortalized "normal" oral keratinocytes (NOKs) we generated clonal cell lines maintaining the HPV16 genome as an episome, NOKs+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 NOKs+HPV16. We show that the behavior of these NOKs+HPV16 lines is identical to HPV16 immortalized human tonsil keratinocytes with regards innate gene regulation. Finally, us...Continue Reading

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Citations

Apr 9, 2019·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Sally RobertsJoanna L Parish
Jul 12, 2019·Journal of Virology·Gaurav RaikhyJason M Bodily
Jun 28, 2019·Current Protein & Peptide Science·Eskandar TaghizadehSeyed Mohammad Gheibi Hayat
Mar 22, 2019·Proceedings of the National Academy of Sciences of the United States of America·Joshua HatterschideElizabeth A White

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Methods Mentioned

BETA
RNA-seq
PCR
transfection
protein estimation assay
chip

Software Mentioned

ZEN
bowtie2
cBot
DESeq2
Ensembl
Samtools

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