Beta genus papillomaviruses and skin cancer

Howley, Peter M.; Pfister, Herbert

doi:10.1016/j.virol.2015.02.004

Cited by 163 publications

(201 citation statements)

References 76 publications

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“…On the basis of biologic and epidemiologic data, some HPV types within the beta-1 and beta-2 species are likely to be involved, together with UV irradiation, in the development of NMSC (2,3,22). However, very little is known about the biology of most beta HPV types and whether they are linked to additional human diseases.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to alpha HPV types, the epidemiology and biology of beta HPV types have been poorly investigated to date. Beta HPV types, namely beta-1 HPV5 and HPV8, were first isolated from individuals with an autosomal-recessive disorder termed epidermodysplasia verruciformis (3). These individuals are susceptible to infection by beta HPV types and prone to developing squamous cell carcinoma (SCC) on sun-exposed areas.…”

Section: Introductionmentioning

confidence: 99%

“…These individuals are susceptible to infection by beta HPV types and prone to developing squamous cell carcinoma (SCC) on sun-exposed areas. More recent studies indicate that beta HPV types are also involved, together with UV radiation, in skin carcinogenesis in the normal population (3). In particular, SCC development appears to be linked mainly to HPV types within the beta-1 and beta-2 species.…”

Section: Introductionmentioning

confidence: 99%

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Novel ß-HPV49 Transgenic Mouse Model of Upper Digestive Tract Cancer

et al. 2016

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The beta genus of human papillomaviruses (ß-HPV) includes approximately 50 different viral types that are subdivided into five species (ß-1 through ß-5). Nonmelanoma cancers may involve some ß-1 and ß-2 HPV types, but the biology of most ß-HPV types and their possible connections to human disease are still little characterized. In this study, we studied the effects of ß-3 type HPV49 in a novel transgenic (Tg) mouse model, using a cytokeratin K14 promoter to drive expression of the E6 and E7 genes from this virus in the basal skin epidermis and the mucosal epithelia of the digestive tract (K14 HPV49 E6/E7-Tg mice). Viral oncogene expression only marginally increased cellular proliferation in the epidermis of Tg animals, compared with wild-type littermates, and we observed no spontaneous tumor formation during their entire lifespan. However, we found that K14 HPV49 E6/E7-Tg mice were highly susceptible to upper digestive tract carcinogenesis upon initiation with 4-nitroquinoline 1-oxide (4NQO). This was a selective effect, as the same mice did not exhibit any skin lesions after chronic UV irradiation. Opposite results were observed in an analogous Tg model expressing the ß-2 HPV38 E6 and E7 oncogenes at the same anatomic sites. While these mice were highly susceptible to UV-induced skin carcinogenesis, as previously shown, they were little affected by 4NQO treatment. Overall, our findings highlight important differences in the biologic properties of certain ß-type HPV that affect their impact on carcinogenesis in an anatomic site-specific manner.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel ß-HPV49 Transgenic Mouse Model of Upper Digestive Tract Cancer

et al. 2016

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“…Journal of Virology (9,15). Transgenic mice expressing beta HPV oncoproteins under the control of the keratin 14 promoter showed higher susceptibility to UV-induced carcinogenesis than did wild-type animals (16).…”

Section: Hpv38 E6 and E7 Inhibit Uv-induced Tlr9 Expressionmentioning

confidence: 99%

UV Radiation Activates Toll-Like Receptor 9 Expression in Primary Human Keratinocytes, an Event Inhibited by Human Papillomavirus 38 E6 and E7 Oncoproteins

Pacini

Ceraolo

Venuti

et al. 2017

J Virol

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Several lines of evidence indicate that cutaneous human papillomavirus (HPV) types belonging to the beta genus of the HPV phylogenetic tree synergize with UV radiation in the development of skin cancer. Accordingly, the E6 and E7 oncoproteins from some beta HPV types are able to deregulate pathways related to immune response and cellular transformation. Toll-like receptor 9 (TLR9), in addition to playing a role in innate immunity, has been shown to be involved in the cellular stress response. Using primary human keratinocytes as experimental models, we have shown that UV irradiation (and other cellular stresses) activates TLR9 expression. This event is closely linked to p53 activation. Silencing the expression of p53 or deleting its encoding gene affected the activation of TLR9 expression after UV irradiation. Using various strategies, we have also shown that the transcription factors p53 and c-Jun are recruited onto a specific region of the TLR9 promoter after UV irradiation. Importantly, the E6 and E7 oncoproteins from beta HPV38, by inducing the accumulation of the p53 antagonist ΔNp73␣, prevent the UV-mediated recruitment of these transcription factors onto the TLR9 promoter, with subsequent impairment of TLR9 gene expression. This study provides new insight into the mechanism that mediates TLR9 upregulation in response to cellular stresses. In addition, we show that HPV38 E6 and E7 are able to interfere with this mechanism, providing another explanation for the possible cooperation of beta HPV types with UV radiation in skin carcinogenesis.IMPORTANCE Beta HPV types have been suggested to act as cofactors in UVinduced skin carcinogenesis by altering several cellular mechanisms activated by UV radiation. We show that the expression of TLR9, a sensor of damage-associated molecular patterns produced during cellular stress, is activated by UV radiation in primary human keratinocytes (PHKs). Two transcription factors known to be activated by UV radiation, p53 and c-Jun, play key roles in UV-activated TLR9 expression. The E6 and E7 oncoproteins from beta HPV38 strongly inhibit UV-activated TLR9 expression by preventing the recruitment of p53 and c-Jun to the TLR9 promoter. Our findings provide additional support for the role that beta HPV types play in skin carcinogenesis by preventing activation of specific pathways upon exposure of PHKs to UV radiation.KEYWORDS UV radiation, Toll-like receptor 9, HPV38, primary keratinocytes, p53

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“…HPV5 and HPV8 are among the most frequently found types in lesions of EV patients, but many other b-HPV types have also been identified in such lesions (Akgül et al, 2007b;Cardoso & Calonje, 2011). In the general population, b-HPV are suspected to have an aetiological role in skin carcinogenesis as well, but this is still a matter of controversial discussion (Howley & Pfister, 2015;Quint et al, 2015;Smola, 2014). The oncogenic potential of HPV8 early proteins has been investigated in mouse models and in vitro organotypic skin cultures (OSC) of primary human keratinocytes (PHK).…”

Section: Introductionmentioning

confidence: 99%

The levels of epithelial anchor proteins β-catenin and zona occludens-1 are altered by E7 of human papillomaviruses 5 and 8

Heuser

Hufbauer

Marx

et al. 2016

Journal of General Virology

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Infection with viruses of the genus Betapapillomavirus, b-human papillomaviruses (b-HPV), is implicated in the development of non-melanoma skin cancer. This was first evidenced for HPV5 and HPV8 in patients with the skin disease epidermodysplasia verruciformis (EV). The relocalization of the junctional bridging proteins b-catenin and zona occludens-1 (ZO-1) from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumour invasion. Here, we report that b-catenin and ZO-1 are strongly upregulated by the E7 oncoproteins of HPV5 and HPV8 in keratinocytes grown in organotypic skin cultures. Although the membrane-tethered form of b-catenin was elevated, no signs of b-catenin activity within the canonical Wnt signalling pathway could be detected. The upregulation of b-catenin and ZO-1 could also be confirmed in the skin of HPV8 transgenic mice as well as in cutaneous squamous cell carcinomas of EV patients. These data provide the first evidence that b-catenin and ZO-1 are direct targets of E7 of the oncogenic b-HPV types 5 and 8. The ability to deregulate these epithelial junction proteins may contribute to the oncogenic potential of these viruses in human skin.

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Beta genus papillomaviruses and skin cancer

Cited by 163 publications

References 76 publications

Novel ß-HPV49 Transgenic Mouse Model of Upper Digestive Tract Cancer

Novel ß-HPV49 Transgenic Mouse Model of Upper Digestive Tract Cancer

UV Radiation Activates Toll-Like Receptor 9 Expression in Primary Human Keratinocytes, an Event Inhibited by Human Papillomavirus 38 E6 and E7 Oncoproteins

The levels of epithelial anchor proteins β-catenin and zona occludens-1 are altered by E7 of human papillomaviruses 5 and 8

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