Virus transcript levels and cell growth rates after naturally occurring <scp>HPV16</scp> integration events in basal cervical keratinocytes

Scarpini, Cinzia G.; Groves, Ian; Pett, Mark R.; Ward, Dawn

doi:10.1002/path.4358

Cited by 22 publications

(66 citation statements)

References 43 publications

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“…Analysis of 35 TCGA samples of HNSCC showed that cases with integrated HRHPV (n = 25) generally had a higher E6/E7 transcript level per cell than those with episomal HRHPV (n = 10) [9]. Interestingly, however, the presence of integrated genomes did not always correlate with high virus transcription, in keeping with the findings of other studies [12,36,37] and our previous work using the W12 cell model of cervical squamous carcinogenesis [38][39][40]. Hence, SCC is not always associated with high virus oncogene expression levels, and may be driven independently of this factor, e.g.…”

Section: Hpv Oncogene Expressionsupporting

confidence: 85%

Human papillomavirus genome integration in squamous carcinogenesis: what have next‐generation sequencing studies taught us?

Groves

Coleman

2018

The Journal of Pathology

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Human papillomavirus (HPV) infection is associated with ∼5% of all human cancers, including a range of squamous cell carcinomas. Persistent infection by high-risk HPVs (HRHPVs) is associated with the integration of virus genomes (which are usually stably maintained as extrachromosomal episomes) into host chromosomes. Although HRHPV integration rates differ across human sites of infection, this process appears to be an important event in HPV-associated neoplastic progression, leading to deregulation of virus oncogene expression, host gene expression modulation, and further genomic instability. However, the mechanisms by which HRHPV integration occur and by which the subsequent gene expression changes take place are incompletely understood. The advent of next-generation sequencing (NGS) of both RNA and DNA has allowed powerful interrogation of the association of HRHPVs with human disease, including precise determination of the sites of integration and the genomic rearrangements at integration loci. In turn, these data have indicated that integration occurs through two main mechanisms: looping integration and direct insertion. Improved understanding of integration sites is allowing further investigation of the factors that provide a competitive advantage to some integrants during disease progression. Furthermore, advanced approaches to the generation of genome-wide samples have given novel insights into the three-dimensional interactions within the nucleus, which could act as another layer of epigenetic control of both virus and host transcription. It is hoped that further advances in NGS techniques and analysis will not only allow the examination of further unanswered questions regarding HPV infection, but also direct new approaches to treating HPV-associated human disease.

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Section: Hpv Oncogene Expressionsupporting

confidence: 85%

Human papillomavirus genome integration in squamous carcinogenesis: what have next‐generation sequencing studies taught us?

Groves

Coleman

2018

The Journal of Pathology

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“…In the context of the neoplastic progression, acetylation of H3 increases as the cell progresses phenotypically from normal to SCC in both episomal and integration mediated carcinogenesis. H3 lysine 27 trimethylation and H3 lysine 9 trimethylation markers decrease with the neoplastic progression in integration mediated carcinogenesis [99, 100]. …”

Section: Epigenetic Modification In Cervical Cancermentioning

confidence: 99%

Molecular mechanisms of HPV mediated neoplastic progression

Senapati¹,

Senapati²,

Dwibedi³

2016

Infect Agents Cancer

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Human Papillomavirus is the major etiological agent in the development of cervical cancer but not a sufficient cause. Despite significant research, the underlying mechanisms of progression from a low-grade squamous intraepithelial lesion to high grade squamous intraepithelial lesion are yet to be understood. Deregulation of viral gene expression and host genomic instability play a central role in virus-mediated carcinogenesis. Key events such as viral integration and epigenetic modifications may lead to the deregulation of viral and host gene expression. This review has summarized the available literature to describe the possible mechanism and role of viral integration in mediating carcinogenesis. HPV integration begins with DNA damage or double strand break induced either by oxidative stress or HPV proteins and the subsequent steps are driven by the DNA damage responses. Inflammation and oxidative stress could be considered as cofactors in stimulating viral integration and deregulation of cellular and viral oncogenes during the progression of cervical carcinoma. All these events together with the host and viral genetic and epigenetic modifications in neoplastic progression have also been reviewed which may be relevant in identifying a new preventive therapeutic strategy. In the absence of therapeutic intervention for HPV-infected individuals, future research focus should be directed towards preventing and reversing of HPV integration. DNA damage response, knocking out integrated HPV sequences, siRNA approach, modulating the selection mechanism of cells harboring integrated genomes and epigenetic modifiers are the possible therapeutic targets.

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“…Only seven of the clones analysed (41%) showed significantly greater expression of HPV16 E6 and E7 than the episome-containing LSIL-like cells from which they were derived, indicating that HPV integration per se does not necessarily lead to increased levels of virus oncogenes per cell. 17 Interestingly, levels of E6/E7 transcript per DNA template across the clones varied by ~16-fold. 17 …”

Section: Introductionmentioning

confidence: 99%

“…By this method, we derived a series of clones from an identical genetic background that differed only by the site of HPV16 integration into the host genome. The large majority of clones showed no evidence of full-length HPV16 concatemerisation 17 and were therefore so called type I integrants. 2 Several clones contained multiple copies of the E6/E7 oncogenes, consistent with local DNA rearrangements following integration.…”

Section: Introductionmentioning

confidence: 99%

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HPV16 oncogene expression levels during early cervical carcinogenesis are determined by the balance of epigenetic chromatin modifications at the integrated virus genome

et al. 2016

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In cervical squamous cell carcinomas, high-risk human papillomavirus (HRHPV) DNA is usually integrated into host chromosomes. Multiple integration events are thought to be present within the cells of a polyclonal premalignant lesion and the features that underpin clonal selection of one particular integrant remain poorly understood. We previously used the W12 model system to generate a panel of cervical keratinocyte clones, derived from cells of a low-grade premalignant lesion naturally infected with the major HRHPV type, HPV16. The cells were isolated regardless of their selective advantage and differed only by the site of HPV16 integration into the host genome. We used this resource to test the hypothesis that levels of HPV16 E6/E7 oncogene expression in premalignant cells are regulated epigenetically. We performed a comprehensive analysis of the epigenetic landscape of the integrated HPV16 DNA in selected clones, in which levels of virus oncogene expression per DNA template varied ~6.6-fold. Across the cells examined, higher levels of virus expression per template were associated with more open chromatin at the HPV16 long control region, together with greater loading of chromatin remodelling enzymes and lower nucleosome occupancy. There were higher levels of histone post-translational modification hallmarks of transcriptionally active chromatin and lower levels of repressive hallmarks. There was greater abundance of the active/elongating form of the RNA polymerase-II enzyme (RNAPII-Ser2P), together with CDK9, the component of positive transcription elongation factor b complex responsible for Ser2 phosphorylation. The changes observed were functionally significant, as cells with higher HPV16 expression per template showed greater sensitivity to depletion and/or inhibition of histone acetyltransferases and CDK9 and less sensitivity to histone deacetylase inhibition. We conclude that virus gene expression per template following HPV16 integration is determined through multiple layers of epigenetic regulation, which are likely to contribute to selection of individual cells during cervical carcinogenesis.

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Virus transcript levels and cell growth rates after naturally occurring HPV16 integration events in basal cervical keratinocytes

Cited by 22 publications

References 43 publications

Human papillomavirus genome integration in squamous carcinogenesis: what have next‐generation sequencing studies taught us?

Human papillomavirus genome integration in squamous carcinogenesis: what have next‐generation sequencing studies taught us?

Molecular mechanisms of HPV mediated neoplastic progression

HPV16 oncogene expression levels during early cervical carcinogenesis are determined by the balance of epigenetic chromatin modifications at the integrated virus genome

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