Limits...
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.

Show MeSH

Related in: MedlinePlus

Keratinocyte differentiation marker expression in epidermis, vulva and cervix.Immunohistochemical analysis of AKT1, loricrin and keratin 1 expression in extragenital cutaneous epidermis, vulval external epithelium and cervix. Bar 50 µm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369856&req=5

pone-0038608-g001: Keratinocyte differentiation marker expression in epidermis, vulva and cervix.Immunohistochemical analysis of AKT1, loricrin and keratin 1 expression in extragenital cutaneous epidermis, vulval external epithelium and cervix. Bar 50 µm.

Mentions: We compared the expression of AKT1 and loricrin (a differentiation marker expressed in the upper epidermal granular layer) in normal extragenital cutaneous, cervical and vulval epithelia (Figure 1). Extragenital and vulval epidermis had identical expression patterns of AKT1 and loricrin, with expression of both proteins being restricted to the granular layer [13]. In contrast, neither AKT1 nor loricrin were detected in the upper cervical epithelium. Cytokeratin 1 was expressed in all suprabasal layers of all three epithelia. These findings suggest that the squamous keratinising epithelial component of vulval skin is similar to extragenital epidermis and may therefore be similarly susceptible to infection by cutaneous HPV types as well as alpha (mucosal) high risk HPV types.


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)

Keratinocyte differentiation marker expression in epidermis, vulva and cervix.Immunohistochemical analysis of AKT1, loricrin and keratin 1 expression in extragenital cutaneous epidermis, vulval external epithelium and cervix. Bar 50 µm.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038608-g001: Keratinocyte differentiation marker expression in epidermis, vulva and cervix.Immunohistochemical analysis of AKT1, loricrin and keratin 1 expression in extragenital cutaneous epidermis, vulval external epithelium and cervix. Bar 50 µm.
Mentions: We compared the expression of AKT1 and loricrin (a differentiation marker expressed in the upper epidermal granular layer) in normal extragenital cutaneous, cervical and vulval epithelia (Figure 1). Extragenital and vulval epidermis had identical expression patterns of AKT1 and loricrin, with expression of both proteins being restricted to the granular layer [13]. In contrast, neither AKT1 nor loricrin were detected in the upper cervical epithelium. Cytokeratin 1 was expressed in all suprabasal layers of all three epithelia. These findings suggest that the squamous keratinising epithelial component of vulval skin is similar to extragenital epidermis and may therefore be similarly susceptible to infection by cutaneous HPV types as well as alpha (mucosal) high risk HPV types.

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