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Changes in Cervical Keratinocyte Gene Expression Associated with Integration of Human Papillomavirus 16¹

Medical Research Council Cancer Cell Unit, MRC/Hutchison Research Centre, Cambridge CB2 2XZ [W. A., N. C.]; Department of Pathology, University of Cambridge, Cambridge CB2 1QP [M. P., M. A. S., N. C.]; Institute of Public Health, Cambridge CB2 25R [B. A.]; and Medical Research Council Human Genome Mapping Resource Centre, Cambridge CB10 1SB [L. S., T. F.], United Kingdom

Episomal integration is a critical event in human papillomavirus (HPV)-related oncogenesis, although little information is currently available concerning the effect of integration on the host transcriptome. We have used expression microarrays to investigate the effect of integration of HPV16 on gene expression in cervical keratinocytes, using the unique cell line model W12. W12 was generated from a cervical low-grade squamous intraepithelial lesion "naturally" infected with HPV16 and at low passage contains approximately 100 HPV16 episomes/cell. With passage in vitro, integration of viral episomes is associated with the development of phenotypic and genomic abnormalities resembling those seen in cervical neoplastic progression in vivo. We have used the Affymetrix U95A oligonucleotide array that contains probes for 12,600 human transcripts and have identified 85 genes from a range of host cell pathways that show changes in expression levels after integration of HPV16. Whereas some of the genes have previously been implicated in HPV-related oncogenesis in vivo, we have also identified a range of genes not previously described as being involved in cervical neoplastic progression. Interestingly, integration is associated with up-regulation of numerous IFN-responsive genes, in comparison with a baseline of episomally infected cells. These genes include p48, a component of the primary regulator of the IFN response pathway, IFN-stimulated gene factor 3. The physical state of high-risk HPV may substantially influence the response to IFN in infected keratinocytes.

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