Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.

Infection with a transforming human papillomavirus (HPV) such as type 16 (of species Alphapapillomavirus 9) causes ano-genital and oral tumours via viral persistence in human squamous cell epithelia. Epidemiological studies showed that the naturally occurring HPV16 Asian-American (AA) variant (subli...

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Autores principales:	Robert Jackson, Melissa Togtema, Paul F Lambert, Ingeborg Zehbe
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ee339356ddf84158840a66694021dd45
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spelling	oai:doaj.org-article:ee339356ddf84158840a66694021dd452021-11-25T06:10:08ZTumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.1932-620310.1371/journal.pone.0101540https://doaj.org/article/ee339356ddf84158840a66694021dd452014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24983759/?tool=EBIhttps://doaj.org/toc/1932-6203Infection with a transforming human papillomavirus (HPV) such as type 16 (of species Alphapapillomavirus 9) causes ano-genital and oral tumours via viral persistence in human squamous cell epithelia. Epidemiological studies showed that the naturally occurring HPV16 Asian-American (AA) variant (sublineage D2/D3) is found more often than the European Prototype (EP) (sublineage A1) in high-grade cervical neoplasia and tumours compared to non-cancer controls. Just three amino acid changes within the early gene, E6, of HPV16 AA have been linked to this augmented tumourigenicity. The AAE6 variant's greater immortalizing and transforming potential over EPE6 has recently been confirmed in retrovirally-transduced keratinocytes expressing the E6 gene only. However, the tumourigenic role of the full-length viral genome of HPV16 has not yet been addressed with regard to these E6 variants. To investigate this process in the context of these two HPV16 E6 genotypes, an organotypic tissue culture model was used to simulate the HPV infectious life cycle. The AAE6 variant demonstrated an enhanced ability over EPE6 to drive the viral life cycle toward tumourigenesis, as evidenced phenotypically-by a more severe grade of epithelial dysplasia with higher proliferation and deregulated differentiation, and molecularly-by high viral oncogene E6 and E7 expression, but lack of productive viral life cycle markers. In contrast, EPE6 had low E6 and E7 but high E1∧E4 expression, indicative of a productive life cycle. We suggest increased viral integration into the host genome for AAE6 as one possible mechanism for these observed differences from EPE6. Additionally, we found downstream effects on immortalization and host innate immune evasion. This study highlights how minor genomic variations in transforming viruses can have a significant affect on their tumourigenic ability.Robert JacksonMelissa TogtemaPaul F LambertIngeborg ZehbePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e101540 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Robert Jackson Melissa Togtema Paul F Lambert Ingeborg Zehbe Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.
description	Infection with a transforming human papillomavirus (HPV) such as type 16 (of species Alphapapillomavirus 9) causes ano-genital and oral tumours via viral persistence in human squamous cell epithelia. Epidemiological studies showed that the naturally occurring HPV16 Asian-American (AA) variant (sublineage D2/D3) is found more often than the European Prototype (EP) (sublineage A1) in high-grade cervical neoplasia and tumours compared to non-cancer controls. Just three amino acid changes within the early gene, E6, of HPV16 AA have been linked to this augmented tumourigenicity. The AAE6 variant's greater immortalizing and transforming potential over EPE6 has recently been confirmed in retrovirally-transduced keratinocytes expressing the E6 gene only. However, the tumourigenic role of the full-length viral genome of HPV16 has not yet been addressed with regard to these E6 variants. To investigate this process in the context of these two HPV16 E6 genotypes, an organotypic tissue culture model was used to simulate the HPV infectious life cycle. The AAE6 variant demonstrated an enhanced ability over EPE6 to drive the viral life cycle toward tumourigenesis, as evidenced phenotypically-by a more severe grade of epithelial dysplasia with higher proliferation and deregulated differentiation, and molecularly-by high viral oncogene E6 and E7 expression, but lack of productive viral life cycle markers. In contrast, EPE6 had low E6 and E7 but high E1∧E4 expression, indicative of a productive life cycle. We suggest increased viral integration into the host genome for AAE6 as one possible mechanism for these observed differences from EPE6. Additionally, we found downstream effects on immortalization and host innate immune evasion. This study highlights how minor genomic variations in transforming viruses can have a significant affect on their tumourigenic ability.
format	article
author	Robert Jackson Melissa Togtema Paul F Lambert Ingeborg Zehbe
author_facet	Robert Jackson Melissa Togtema Paul F Lambert Ingeborg Zehbe
author_sort	Robert Jackson
title	Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.
title_short	Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.
title_full	Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.
title_fullStr	Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.
title_full_unstemmed	Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.
title_sort	tumourigenesis driven by the human papillomavirus type 16 asian-american e6 variant in a three-dimensional keratinocyte model.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/ee339356ddf84158840a66694021dd45
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Tumourigenesis driven by the human papillomavirus type 16 Asian-American e6 variant in a three-dimensional keratinocyte model.

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