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AKT1 loss correlates with episomal HPV16 in vulval intraepithelial neoplasia.

Ekeowa-Anderson AL, Purdie KJ, Gibbon K, Byrne CR, Arbeit JM, Harwood CA, O'Shaughnessy RF - PLoS ONE (2012)

Bottom Line: Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers.We show that HPV16 early gene expression reduced AKT1 expression in transgenic mouse epidermis.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

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.

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AKT1 expression is lost in a subset of VIN and the epidermis of the K14-HPV16 mouse.A. Histology and AKT1 expression in two representative VIN. Inset shows specific AKT1 expression associated with nucleated upper epidermal cells. Secondary alone control of upper epidermis is also shown. B. Immunohistochemical analysis of AKT1 in the dorsal epidermis of the K14-HPV8 complete early region (CER) and ear epidermis of the K14-HPV16 complete early region mouse and corresponding wildtype controls (wildtype). Arrowheads indicate AKT1 positivity in the granular layer of controls. Sec alone is a no primary antibody control for staining specificity. Bar (A–B) 50 µm.
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pone-0038608-g002: AKT1 expression is lost in a subset of VIN and the epidermis of the K14-HPV16 mouse.A. Histology and AKT1 expression in two representative VIN. Inset shows specific AKT1 expression associated with nucleated upper epidermal cells. Secondary alone control of upper epidermis is also shown. B. Immunohistochemical analysis of AKT1 in the dorsal epidermis of the K14-HPV8 complete early region (CER) and ear epidermis of the K14-HPV16 complete early region mouse and corresponding wildtype controls (wildtype). Arrowheads indicate AKT1 positivity in the granular layer of controls. Sec alone is a no primary antibody control for staining specificity. Bar (A–B) 50 µm.

Mentions: We wanted to establish whether AKT1 is down-regulated similar to non-genital skin or up-regulated, potentially due to alpha-PV. We therefore analysed HPV types present in 14 snap-frozen high-grade VIN (Histological grade 2 and 3) (Table 1), correlating this with AKT1 loss. AKT1 expression was examined by immunohistochemistry ([13]; Figure 2A). AKT1 was lost in 6/14 (42%) of VIN, and HPV16 was present in 11/14 (78%) samples. Five of the 6 (83%) AKT1 negative VIN were HPV16 positive, while 6/8 (75%) of AKT1 positive VIN were HPV16 positive (n.s., Fishers exact test). Beta-PV types were detected in 2/14 (14%, one AKT1 positive, one AKT1 negative, Table 1). Although the RHA assay is non-quantitative, the weakness of the beta-PV signals compared to HPV16 signals was consistent with beta-PV being present at very low copy number (data not shown). Note that no other HPV types were detected by this analysis (data not shown). We concluded that beta-PV were unlikely to be significant aetiological agents in VIN.


AKT1 loss correlates with episomal HPV16 in vulval intraepithelial neoplasia.

Ekeowa-Anderson AL, Purdie KJ, Gibbon K, Byrne CR, Arbeit JM, Harwood CA, O'Shaughnessy RF - PLoS ONE (2012)

AKT1 expression is lost in a subset of VIN and the epidermis of the K14-HPV16 mouse.A. Histology and AKT1 expression in two representative VIN. Inset shows specific AKT1 expression associated with nucleated upper epidermal cells. Secondary alone control of upper epidermis is also shown. B. Immunohistochemical analysis of AKT1 in the dorsal epidermis of the K14-HPV8 complete early region (CER) and ear epidermis of the K14-HPV16 complete early region mouse and corresponding wildtype controls (wildtype). Arrowheads indicate AKT1 positivity in the granular layer of controls. Sec alone is a no primary antibody control for staining specificity. Bar (A–B) 50 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369856&req=5

pone-0038608-g002: AKT1 expression is lost in a subset of VIN and the epidermis of the K14-HPV16 mouse.A. Histology and AKT1 expression in two representative VIN. Inset shows specific AKT1 expression associated with nucleated upper epidermal cells. Secondary alone control of upper epidermis is also shown. B. Immunohistochemical analysis of AKT1 in the dorsal epidermis of the K14-HPV8 complete early region (CER) and ear epidermis of the K14-HPV16 complete early region mouse and corresponding wildtype controls (wildtype). Arrowheads indicate AKT1 positivity in the granular layer of controls. Sec alone is a no primary antibody control for staining specificity. Bar (A–B) 50 µm.
Mentions: We wanted to establish whether AKT1 is down-regulated similar to non-genital skin or up-regulated, potentially due to alpha-PV. We therefore analysed HPV types present in 14 snap-frozen high-grade VIN (Histological grade 2 and 3) (Table 1), correlating this with AKT1 loss. AKT1 expression was examined by immunohistochemistry ([13]; Figure 2A). AKT1 was lost in 6/14 (42%) of VIN, and HPV16 was present in 11/14 (78%) samples. Five of the 6 (83%) AKT1 negative VIN were HPV16 positive, while 6/8 (75%) of AKT1 positive VIN were HPV16 positive (n.s., Fishers exact test). Beta-PV types were detected in 2/14 (14%, one AKT1 positive, one AKT1 negative, Table 1). Although the RHA assay is non-quantitative, the weakness of the beta-PV signals compared to HPV16 signals was consistent with beta-PV being present at very low copy number (data not shown). Note that no other HPV types were detected by this analysis (data not shown). We concluded that beta-PV were unlikely to be significant aetiological agents in VIN.

Bottom Line: Dysregulation of AKT, a serine/threonine kinase, plays a significant role in several cancers.We show that HPV16 early gene expression reduced AKT1 expression in transgenic mouse epidermis.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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus