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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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Related in: MedlinePlus

Early gene expression in VIN.Expression of the early genes 16E1∧E4 and 16E7 in a representative AKT1 negative (AKT1 −ve) and AKT1 positive (AKT1 +ve) VIN. Note the increased 16E7 expression in AKT1 positive VIN, and the change of 16E1∧E4 expression from perinuclear low expression in AKT1 negative VIN to high nuclear expression in AKT1 positive VIN (see insets). Bar 50µm.
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pone-0038608-g003: Early gene expression in VIN.Expression of the early genes 16E1∧E4 and 16E7 in a representative AKT1 negative (AKT1 −ve) and AKT1 positive (AKT1 +ve) VIN. Note the increased 16E7 expression in AKT1 positive VIN, and the change of 16E1∧E4 expression from perinuclear low expression in AKT1 negative VIN to high nuclear expression in AKT1 positive VIN (see insets). Bar 50µm.

Mentions: To determine whether integration events correlated with changes in early gene expression, we examined 8 VIN for HPV16 E7 and E1∧E4 expression. HPV16 E7 is normally up-regulated after integration of HPV16 [20]. HPV16 E1∧E4 accumulates in mitochondria, clumping them in a region close to the nucleus [21] and on HPV16 integration is frequently truncated causing nuclear accumulation [22]. In HPV16 and AKT1 positive VIN, E7 expression was high and widespread not only in the nucleus, as has been reported previously in cervical cancer, but also in the cytoplasm in some VIN [23]. E1∧E4 expression was widespread and nuclear. In HPV16 positive and AKT1 negative VIN, E7 expression was lower and E1∧E4 was restricted to the perinuclear region in a few cells (Figure 3) suggesting again that AKT1 positivity correlates with life cycle events consistent with HPV16 integration 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)

Early gene expression in VIN.Expression of the early genes 16E1∧E4 and 16E7 in a representative AKT1 negative (AKT1 −ve) and AKT1 positive (AKT1 +ve) VIN. Note the increased 16E7 expression in AKT1 positive VIN, and the change of 16E1∧E4 expression from perinuclear low expression in AKT1 negative VIN to high nuclear expression in AKT1 positive VIN (see insets). Bar 50µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038608-g003: Early gene expression in VIN.Expression of the early genes 16E1∧E4 and 16E7 in a representative AKT1 negative (AKT1 −ve) and AKT1 positive (AKT1 +ve) VIN. Note the increased 16E7 expression in AKT1 positive VIN, and the change of 16E1∧E4 expression from perinuclear low expression in AKT1 negative VIN to high nuclear expression in AKT1 positive VIN (see insets). Bar 50µm.
Mentions: To determine whether integration events correlated with changes in early gene expression, we examined 8 VIN for HPV16 E7 and E1∧E4 expression. HPV16 E7 is normally up-regulated after integration of HPV16 [20]. HPV16 E1∧E4 accumulates in mitochondria, clumping them in a region close to the nucleus [21] and on HPV16 integration is frequently truncated causing nuclear accumulation [22]. In HPV16 and AKT1 positive VIN, E7 expression was high and widespread not only in the nucleus, as has been reported previously in cervical cancer, but also in the cytoplasm in some VIN [23]. E1∧E4 expression was widespread and nuclear. In HPV16 positive and AKT1 negative VIN, E7 expression was lower and E1∧E4 was restricted to the perinuclear region in a few cells (Figure 3) suggesting again that AKT1 positivity correlates with life cycle events consistent with HPV16 integration 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