Journal article
Interferon treatment of human keratinocytes harboring extrachromosomal, persistent HPV-16 plasmid genomes induces de novo viral integration
Carcinogenesis (New York), Vol.36(1), pp.151-159
01/2015
DOI: 10.1093/carcin/bgu236
PMID: 25416558
Abstract
Interferons (IFNs) have been used to treat epithelial lesions caused by human papillomavirus (HPV) persistence. Here, we exposed primary human keratinocytes (HFKs) immortalized by persistently replicating HPV-16 plasmid genomes to increasing levels of IFN-γ. While untreated HFKs retained replicating HPV-16 plasmids for up to 60-120 population doublings, IFN led to rapid HPV-16 plasmid loss. However, treated cultures eventually gave rise to outgrowth of clones harboring integrated HPV-16 genomes expressing viral E6 and E7 oncogenes from chimeric virus-cell mRNAs similar to those in cervical and head and neck cancers. Surprisingly, every HPV-16 integrant that arose after IFN exposure stemmed from an independent integration event into a different cellular gene locus, even within parallel cultures started from small cell inocula and cultured separately for ≥ 25 doublings to permit the rise and expansion of spontaneous integrants. While IFN treatment conferred a growth advantage upon preexisting integrants added to mixed control cultures, our results indicate that IFN exposure directly or indirectly induces HPV-16 integration, rather than only selects preexisting, spontaneous integrants that appear to be much less frequent. We estimate that IFN exposure increased integration rates by ≥ 100-fold. IFN-induced HPV-16 integration involved a wide range of chromosomal loci with less apparent selection for recurrent insertions near genes involved in cancer-related pathways. We conclude that IFNs and other potential treatments targeting high-risk HPV persistence that disrupt viral genome replication may promote increased high-risk HPV integration as a step in cancer progression. Therapies against high-risk HPV persistence thus need to be evaluated for their integration-inducing potential.
Details
- Title: Subtitle
- Interferon treatment of human keratinocytes harboring extrachromosomal, persistent HPV-16 plasmid genomes induces de novo viral integration
- Creators
- Michael J Lace - Veterans Affairs Healthcare System and The Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA michael-lace@uiowa.eduJames R Anson - Veterans Affairs Healthcare System andThomas H Haugen - Veterans Affairs Healthcare System and The Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USAJason M Dierdorff - Veterans Affairs Healthcare System andLubomir P Turek - Veterans Affairs Healthcare System and The Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Carcinogenesis (New York), Vol.36(1), pp.151-159
- Publisher
- England
- DOI
- 10.1093/carcin/bgu236
- PMID
- 25416558
- ISSN
- 0143-3334
- eISSN
- 1460-2180
- Language
- English
- Date published
- 01/2015
- Academic Unit
- Pathology; Internal Medicine
- Record Identifier
- 9984047756902771
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