Ekeowa-Anderson, AL;
Purdie, KJ;
Gibbon, K;
Byrne, CR;
Arbeit, JM;
Harwood, CA;
O'Shaughnessy, RF;
(2012)
AKT1 loss correlates with episomal HPV16 in vulval intraepithelial neoplasia.
PLoS One
, 7
(6)
, Article e38608. 10.1371/journal.pone.0038608.
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Abstract
Anogenital malignancy has a significant association with high-risk mucosal alpha-human papillomaviruses (alpha-PV), particularly HPV 16 and 18 whereas extragenital SCC has been linked to the presence of cutaneous beta and gamma-HPV types. Vulval skin may be colonised by both mucosal and cutaneous (beta-, mu-, nu- and gamma-) PV types, but there are few systematic studies investigating their presence and their relative contributions to vulval malignancy. Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers. Mucosal HPV types can increase AKT phosphorylation and activity whereas cutaneous HPV types down-regulate AKT1 expression, probably to weaken the cornified envelope to promote viral release. We assessed the presence of mucosal and cutaneous HPV in vulval malignancy and its relationship to AKT1 expression in order to establish the corresponding HPV and AKT1 profile of normal vulval skin, vulval intraepithelial neoplasia (VIN) and vulval squamous cell carcinoma (vSCC). We show that HPV16 is the principle HPV type present in VIN, there were few detectable beta types present and AKT1 loss was not associated with the presence of these cutaneous HPV. We show that HPV16 early gene expression reduced AKT1 expression in transgenic mouse epidermis. AKT1 loss in our VIN cohort correlated with presence of high copy number, episomal HPV16. Maintained AKT1 expression correlated with low copy number, an increased frequency of integration and increased HPV16E7 expression, a finding we replicated in another untyped cohort of vSCC. Since expression of E7 reflects tumour progression, these findings suggest that AKT1 loss associated with episomal HPV16 may have positive prognostic implications in vulval malignancy.
| Type: | Article |
|---|---|
| Title: | AKT1 loss correlates with episomal HPV16 in vulval intraepithelial neoplasia. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0038608 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0038608 |
| Language: | English |
| Additional information: | This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. PMCID: PMC3369856 ROS is funded by the Wellcome Trust and Barts and the London Charitable Foundation, CB is funded by Cancer Research UK, KJP and CAH are funded by Cancer Research UK, the British Skin Foundation and Barts and the London Charitable Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | Animals, Carcinoma, Squamous Cell, Cohort Studies, DNA, Viral, Disease Progression, Female, Gene Dosage, Host-Pathogen Interactions, Human papillomavirus 16, Humans, Immunohistochemistry, Mice, Mice, Transgenic, Papillomavirus E7 Proteins, Papillomavirus Infections, Polymerase Chain Reaction, Proto-Oncogene Proteins c-akt, Uterine Cervical Neoplasms, Vulva, Vulvar Neoplasms |
| UCL classification: | UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1352257 |
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