RESUMO
Epidermodysplasia verruciformis (EV) is a rare genetic skin disorder that is characterized by the development of papillomavirus-induced skin lesions that can progress to squamous cell carcinoma (SCC). Certain high-risk, cutaneous ß-genus human papillomaviruses (ß-HPVs), in particular HPV5 and HPV8, are associated with inducing EV in individuals who have a homozygous mutation in one of three genes tied to this disease: EVER1, EVER2, or CIB1. EVER1 and EVER2 are also known as TMC6 and TMC8, respectively. Little is known about the biochemical activities of EVER gene products or their roles in facilitating EV in conjunction with ß-HPV infection. To investigate the potential effect of EVER genes on papillomavirus infection, we pursued in vivo infection studies by infecting Ever2-null mice with mouse papillomavirus (MmuPV1). MmuPV1 shares characteristics with ß-HPVs including similar genome organization, shared molecular activities of their early, E6 and E7, oncoproteins, the lack of a viral E5 gene, and the capacity to cause skin lesions that can progress to SCC. MmuPV1 infections were conducted both in the presence and absence of UVB irradiation, which is known to increase the risk of MmuPV1-induced pathogenesis. Infection with MmuPV1 induced skin lesions in both wild-type and Ever2-null mice with and without UVB. Many lesions in both genotypes progressed to malignancy, and the disease severity did not differ between Ever2-null and wild-type mice. However, somewhat surprisingly, lesion growth and viral transcription was decreased, and lesion regression was increased in Ever2-null mice compared with wild-type mice. These studies demonstrate that Ever2-null mice infected with MmuPV1 do not exhibit the same phenotype as human EV patients infected with ß-HPVs.IMPORTANCEHumans with homozygous mutations in the EVER2 gene develop epidermodysplasia verruciformis (EV), a disease characterized by predisposition to persistent ß-genus human papillomavirus (ß-HPV) skin infections, which can progress to skin cancer. To investigate how EVER2 confers protection from papillomaviruses, we infected the skin of homozygous Ever2-null mice with mouse papillomavirus MmuPV1. Like in humans with EV, infected Ever2-null mice developed skin lesions that could progress to cancer. Unlike in humans with EV, lesions in these Ever2-null mice grew more slowly and regressed more frequently than in wild-type mice. MmuPV1 transcription was higher in wild-type mice than in Ever2-null mice, indicating that mouse EVER2 does not confer protection from papillomaviruses. These findings suggest that there are functional differences between MmuPV1 and ß-HPVs and/or between mouse and human EVER2.
Assuntos
Epidermodisplasia Verruciforme , Camundongos Knockout , Infecções por Papillomavirus , Animais , Camundongos , Epidermodisplasia Verruciforme/virologia , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/patologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Betapapillomavirus/genética , Betapapillomavirus/patogenicidade , Humanos , Suscetibilidade a Doenças , Feminino , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Neoplasias Cutâneas/virologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/genéticaAssuntos
Antineoplásicos , Antivirais , Neoplasias do Ânus , Betapapillomavirus , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Humanos , Antineoplásicos/uso terapêutico , Antivirais/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/virologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/virologia , Receptores CXCR4/antagonistas & inibidores , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/virologia , Doenças da Imunodeficiência Primária/tratamento farmacológico , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/virologia , Verrugas/tratamento farmacológico , Verrugas/genética , Verrugas/virologia , Mutação com Ganho de FunçãoRESUMO
CONTEXT.: There have been exceedingly few reports of epidermodysplasia verruciformis (EV) or EV-like lesions in the vulva. We describe the first observation of vulvar lesions displaying synchronous EV-like histology and conventional high-grade squamous intraepithelial lesion (HSIL), a finding hitherto unreported in medical literature. OBJECTIVES.: To describe this novel vulvar lesion with hybrid features of HSIL and EV, attempt to confirm the hypothesis of coinfection with α and ß human papillomavirus (α-HPV and ß-HPV) genotypes, and describe relevant underlying genetic mutations. DESIGN.: Cases were retrospectively selected from our institutional archive. Detailed review of clinical information, histologic examination, and whole genome sequencing (WGS) were performed. RESULTS.: Five samples from 4 different patients were included. Three of 4 patients had a history of either iatrogenic immune suppression or prior immune deficiency, and all 3 featured classic HSIL and EV changes within the same lesion. One patient had no history of immune disorders, presented with EV-like changes and multinucleated atypia of the vulva, and was the sole patient without conventional HSIL. By WGS, several uniquely mappable reads pointed toward infection with multiple HPV genotypes, including both α-HPVs and ß-HPVs. Mutations in genes implicated in cell-mediated immunity, such as DOCK8, CARMIL2, MST1, and others, were also found. CONCLUSIONS.: We provide the first description of vulvar lesions harboring simultaneous HSIL and EV features in the English-language literature, a phenomenon explained by coinfection with α-HPV and ß-HPV genotypes. The finding of EV-like changes in a vulvar specimen should prompt assessment of the patient's immune status.
Assuntos
Alphapapillomavirus , Coinfecção , Epidermodisplasia Verruciforme , Genótipo , Mutação , Infecções por Papillomavirus , Humanos , Feminino , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/virologia , Epidermodisplasia Verruciforme/patologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Estudos Retrospectivos , Alphapapillomavirus/genética , Adulto , Coinfecção/virologia , Coinfecção/genética , Coinfecção/patologia , Neoplasias Vulvares/virologia , Neoplasias Vulvares/genética , Neoplasias Vulvares/patologia , Pessoa de Meia-Idade , Betapapillomavirus/genética , Vulva/patologia , Vulva/virologia , Lesões Intraepiteliais Escamosas/virologia , Lesões Intraepiteliais Escamosas/patologia , Lesões Intraepiteliais Escamosas/genética , Papillomavirus HumanoRESUMO
Human papillomaviruses (HPV) of the genus Betapapillomavirus can infect both cutaneous and mucosal sites, but research on their natural history at mucosal sites remains scarce. We examined the risk factors and co-detection patterns of HPVs of the Betapapillomavirus and Alphapapillomavirus genera in cervical samples of the Ludwig-McGill cohort study. We assessed a subset of 505 women from the Ludwig-McGill cohort study from São Paulo, Brazil. Cervical samples over the first year of follow-up were tested for DNA of over 40 alphapapillomavirus types and 43 betapapillomavirus types using a type-specific multiplex genotyping polymerase chain reaction assay. We assessed the risk factors for prevalent and incident betapapillomavirus type detection, and whether types were detected more frequently together than expected assuming independence using permutation tests, logistic regression, and Cox regression. We observed significant within-genus clustering but not cross-genus clustering. Multiple betapapillomavirus types were co-detected in the same sample 2.24 (95% confidence interval [CI]: 1.65-3.29) times more frequently than expected. Conversely, co-detections of alphapapillomavirus and betapapillomavirus types in the same sample occurred only 0.64 (95% CI: 0.51-0.83) times as often as expected under independence. In prospective analyses, positivity to one HPV genus was associated with a nonsignificant lower incidence of detection of types in the other genus. Lifetime number of sex partners and new sex partner acquisition were associated with lower risks of prevalent and incident betapapillomavirus detection. Betapapillomaviruses are commonly found in the cervicovaginal tract. Results suggest potentially different mechanisms of transmission for betapapillomavirus genital infections other than vaginal sex.
Assuntos
Alphapapillomavirus , Betapapillomavirus , Infecções por Papillomavirus , Humanos , Adulto , Feminino , Betapapillomavirus/genética , Alphapapillomavirus/genética , Estudos de Coortes , Infecções por Papillomavirus/epidemiologia , Estudos Prospectivos , Brasil/epidemiologia , Papillomavirus HumanoRESUMO
Approximately 40% of vulvar squamous cell carcinoma (vSCC) cases are etiologically associated with high-risk human papillomaviruses (HPVs) of the alpha genera (α-HPV) that cause other anogenital cancers; however, the etiology of α-HPV-negative vSCC is poorly understood. HPVs of the beta genera (ß-HPV) are risk factors for cutaneous squamous cell carcinoma (cSCC) and may be related to carcinomas originating in other cutaneous sites such as the vulva. In this study, we investigate the presence of ß-HPVs, with an emphasis on p16-negative squamous lesions adjacent to vSCC. We subjected 28 vulvar squamous intraepithelial lesions adjacent to vSCC for comprehensive HPV genotyping, p16 and p53 immunohistochemistry, and consensus morphology review. Selected cases were subjected to qPCR and RNA in situ hybridization. Clinical data were obtained from medical records. ß-HPV DNA was detected in eight of ten p16-negative lesions and three of fourteen p16-positive high-grade squamous intraepithelial lesions. The HPV DNA loads in vulvar squamous intraepithelial lesions ranged between less than 1 HPV DNA copy per cell to more than 100 HPV DNA copies per cell. This is, to the best of our knowledge, the first report of the association of p16-negative vulvar intraepithelial squamous lesions with detection of ß-HPVs. These findings expand possible etiologic mechanisms that may contribute to p16-negative lesions of the vulva.
Assuntos
Betapapillomavirus , Carcinoma in Situ , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias Cutâneas , Lesões Intraepiteliais Escamosas , Neoplasias Vulvares , Feminino , Humanos , Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Vulvares/etiologia , Neoplasias Vulvares/patologia , Papillomavirus Humano , Lesões Intraepiteliais Escamosas/complicações , Papillomaviridae/genéticaRESUMO
Human alphapapillomaviruses (αHPV) infect genital mucosa, and a high-risk subset is a necessary cause of cervical cancer. Licensed L1 virus-like particle (VLP) vaccines offer immunity against the nine most common αHPV associated with cervical cancer and genital warts. However, vaccination with an αHPV L2-based multimer vaccine, α11-88x5, protected mice and rabbits from vaginal and skin challenge with diverse αHPV types. While generally clinically inapparent, human betapapillomaviruses (ßHPV) are possibly associated with cutaneous squamous cell carcinoma (CSCC) in epidermodysplasia verruciformis (EV) and immunocompromised patients. Here we show that α11-88x5 vaccination protected wild type and EV model mice against HPV5 challenge. Passive transfer of antiserum conferred protection independently of Fc receptors (FcR) or Gr-1+ phagocytes. Antisera demonstrated robust antibody titers against ten ßHPV by L1/L2 VLP ELISA and neutralized and protected against challenge by 3 additional ßHPV (HPV49/76/96). Thus, unlike the licensed vaccines, α11-88x5 vaccination elicits broad immunity against αHPV and ßHPV.
Assuntos
Alphapapillomavirus , Betapapillomavirus , Carcinoma de Células Escamosas , Epidermodisplasia Verruciforme , Infecções por Papillomavirus , Vacinas contra Papillomavirus , Neoplasias Cutâneas , Neoplasias do Colo do Útero , Vacinas de Partículas Semelhantes a Vírus , Animais , Betapapillomavirus/genética , Proteínas do Capsídeo , Epidermodisplasia Verruciforme/prevenção & controle , Feminino , Humanos , Soros Imunes , Camundongos , Vacinas contra Papillomavirus/genética , Coelhos , Receptores Fc , VacinaçãoRESUMO
Persistent infections of the skin with the human papillomavirus of genus beta (ß-HPV) in immunocompetent individuals are asymptomatic, but in immunosuppressed patients, ß-HPV infections exhibit much higher viral loads on the skin and are associated with an increased risk of skin cancer. Unlike with HPV16, a high-risk α-HPV, the impact of ß-HPV early genes on the innate immune sensing of viral nucleic acids has not been studied. Here, we used primary skin keratinocytes and U2OS cells expressing HPV8 or distinct HPV8 early genes and well-defined ligands of the nucleic-acid-sensing receptors RIG-I, MDA5, TLR3, and STING to analyze a potential functional interaction. We found that primary skin keratinocytes and U2OS cells expressed RIG-I, MDA5, TLR3, and STING, but not TLR7, TLR8, or TLR9. While HPV16-E6 downregulated the expression of RIG-I, MDA5, TLR3, and STING and, in conjunction with HPV16-E7, effectively suppressed type I IFN in response to MDA5 activation, the presence of HPV8 early genes showed little effect on the expression of these immune receptors, except for HPV8-E2, which was associated with an elevated expression of TLR3. Nevertheless, whole HPV8 genome expression, as well as the selective expression of HPV8-E1 or HPV8-E2, was found to suppress MDA5-induced type I IFN and the proinflammatory cytokine IL-6. Furthermore, RNA isolated from HPV8-E2 expressing primary human keratinocytes, but not control cells, stimulated a type I IFN response in peripheral blood mononuclear cells, indicating that the expression of HPV8-E2 in keratinocytes leads to the formation of stimulatory RNA ligands that require the active suppression of immune recognition. These results identify HPV8-E1 and HPV8-E2 as viral proteins that are responsible for the immune escape of ß-HPV from the innate recognition of viral nucleic acids, a mechanism that may be necessary for establishing persistent ß-HPV infections.
Assuntos
Betapapillomavirus , Helicase IFIH1 Induzida por Interferon/metabolismo , Ácidos Nucleicos , Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Proteínas do Envelope Viral/metabolismo , Betapapillomavirus/genética , Humanos , Queratinócitos , Leucócitos Mononucleares/metabolismo , Ácidos Nucleicos/metabolismo , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/metabolismo , RNA/metabolismo , Receptor 3 Toll-Like/metabolismoRESUMO
SignificanceHigh-risk (HR) human papillomaviruses (HPV) from the genus alpha cause anogenital and oropharyngeal cancers, whereas the contribution of HPV from the genus beta to the development of cutaneous squamous cell cancer is still under debate. HR-HPV genomes display potent immortalizing activity in human keratinocytes, the natural target cell for HPV. This paper shows that immortalization of keratinocytes by the beta-HPV49 genome requires the inactivation of the viral E8^E2 repressor protein and the presence of the E6 and E7 oncoproteins but also of the E1 and E2 replication proteins. This reveals important differences in the carcinogenic properties of HR-HPV and beta-HPV but also warrants further investigations on the distribution and mutation frequencies of beta-HPV in human cancers.
Assuntos
Betapapillomavirus/fisiologia , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno , Queratinócitos/virologia , Infecções por Papillomavirus/virologia , Replicação Viral , Linhagem Celular Transformada , Genoma Viral , Humanos , Queratinócitos/metabolismo , Proteínas Oncogênicas Virais/genética , RNA ViralRESUMO
The beta genus of human papillomaviruses infects cutaneous keratinocytes. Their replication depends on actively proliferating cells and, thus, they conflict with the cellular response to the DNA damage frequently encountered by these cells. This review focus on one of these viruses (HPV8) that counters the cellular response to damaged DNA and mitotic errors by expressing a protein (HPV8 E6) that destabilizes a histone acetyltransferase, p300. The loss of p300 results in broad dysregulation of cell signaling that decreases genome stability. In addition to discussing phenotypes caused by p300 destabilization, the review contains a discussion of the extent to which E6 from other ß-HPVs destabilizes p300, and provides a discussion on dissecting HPV8 E6 biology using mutants.
Assuntos
Betapapillomavirus/metabolismo , Proteína p300 Associada a E1A/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/enzimologia , Infecções por Papillomavirus/genética , Animais , Betapapillomavirus/genética , Proteína p300 Associada a E1A/genética , Instabilidade Genômica , Interações Hospedeiro-Patógeno , Humanos , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/virologia , ProteóliseRESUMO
The DDR is a complex signaling network responsible for the preservation of genomic integrity. Beta human papillomaviruses (ß-HPVs) are able to destabilize the host genome by attenuating the DDR machinery at the molecular scale following expression of the oncogenes E6 and E7. In the event of ß-HPV infection, the E6- and E7-mediated inhibition of the DDR enhances the oncogenicity of UV-induced mutations to enable carcinogenesis in an otherwise immunocompetent host, marking an important mechanistic divergence from the alpha genus of HPVs. In this review, we summarize recent updates to build upon the 'hit-and-run' hypothesis of ß-HPV pathomechanism and highlight strain-dependent variations. Simultaneously, we illuminate points within the ß-HPV-DDR interface that may unravel new insights for HPV viral genetics, genus-specific mechanistic models, and developments in targeted molecular therapy of ß-HPV-related cancers.
Assuntos
Betapapillomavirus/fisiologia , Carcinogênese , Dano ao DNA , Interações entre Hospedeiro e Microrganismos , Infecções por Papillomavirus/genética , Humanos , Proteínas Oncogênicas Virais/genéticaRESUMO
Human papillomavirus (HPV) is a family of viruses divided into five genera: alpha, beta, gamma, mu, and nu. There is an ongoing discussion about whether beta genus HPVs (ß-HPVs) contribute to cutaneous squamous cell carcinoma (cSCC). The data presented here add to this conversation by determining how a ß-HPV E6 protein (ß-HPV 8E6) alters the cellular response to cytokinesis failure. Specifically, cells were observed after cytokinesis failure was induced by dihydrocytochalasin B (H2CB). ß-HPV 8E6 attenuated the immediate toxicity associated with H2CB but did not promote long-term proliferation after H2CB. Immortalization by telomerase reverse transcriptase (TERT) activation also rarely allowed cells to sustain proliferation after H2CB exposure. In contrast, TERT expression combined with ß-HPV 8E6 expression allowed cells to proliferate for months following cytokinesis failure. However, this continued proliferation comes with genome destabilizing consequences. Cells that survived H2CB-induced cytokinesis failure suffered from changes in ploidy.
Assuntos
Betapapillomavirus/genética , Citocinese/genética , Interações Hospedeiro-Patógeno/genética , Proteínas Oncogênicas Virais/genética , Ploidias , Telomerase/genética , Betapapillomavirus/efeitos dos fármacos , Betapapillomavirus/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocalasina B/análogos & derivados , Citocalasina B/farmacologia , Citocinese/efeitos dos fármacos , Prepúcio do Pênis , Regulação da Expressão Gênica , Genoma Humano , Instabilidade Genômica , Humanos , Cariotipagem , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Queratinócitos/virologia , Masculino , Proteínas Oncogênicas Virais/metabolismo , Transdução de Sinais , Telomerase/metabolismoRESUMO
Betapapillomaviruses have been linked to the development of nonmelanoma skin cancers. A great diversity of these viruses in skin specimens requires the use of sensitive and reliable detection methods. There are currently no standardized assays for diagnostic purposes. A combination of several molecular methods has great practical significance and gives the opportunity to broaden the spectrum of detected Beta-HPV types. In the present study, different molecular methods for Beta-HPVs detection and genotyping were used: PCRs with different sets of primers, PCR followed by reverse hybridization and direct sequencing of PCR amplimers; all performed in skin biopsies from lesions and perilesional healthy area of 118 patients with NMSC or precancerous lesions. Beta-HPVs were detected in 41% of 261 biopsies examined. The RHA for 25 types of Beta-HPVs showed a significantly higher sensitivity than PCR-based methods and allowed to detect 172 genotypes in 86 samples, including 39 with multiple infections. The most frequently identified types were HPV23, HPV24 and HPV93. HPV5 and HPV8, considered high-risk carcinogen types, were detected only in a small percentage of samples. Direct sequencing confirmed the presence of Beta-HPV genotypes from outside of RHA panel in the analysed biopsies. This allowed detecting thirty-two additional genotypes in 5 samples, that were positive only in RHA with the universal probe, which failed to identify the virus genotypes. Our findings confirmed the need to apply different methods to detect Beta-HPV infections.
Assuntos
Betapapillomavirus/genética , Infecções por Papillomavirus/diagnóstico , Reação em Cadeia da Polimerase/métodos , Lesões Pré-Cancerosas/diagnóstico , Análise de Sequência de DNA/métodos , Neoplasias Cutâneas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Primers do DNA , DNA Viral/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/virologia , Sensibilidade e Especificidade , Pele/patologia , Neoplasias Cutâneas/patologiaRESUMO
Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer with a complex but not fully understood pathogenesis. Recent research suggests the role of beta human papillomavirus (HPV) types and HPV-associated inflammatory processes in cSCC development. Beta HPV types are components of the normal flora; however, under the influence of certain cofactors, the virus may trigger a malignant process. Dysregulation of the immune system (chronic inflammation and immunosuppression), environmental factors (ultraviolet radiation), and genetic factors are the most important cofactors involved in beta HPV-related carcinogenesis. In addition, the oncoproteins E6 and E7 of beta HPV types differ biochemically from their counterparts in the structure of alpha HPV types, resulting in different mechanisms of action in carcinogenesis. The aim of our manuscript is to present an updated point of view on the involvement of beta HPV types in cSCC pathogenesis.
Assuntos
Betapapillomavirus/fisiologia , Carcinoma de Células Escamosas/virologia , Infecções por Papillomavirus/complicações , Neoplasias Cutâneas/virologia , Betapapillomavirus/genética , Betapapillomavirus/metabolismo , Carcinogênese , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/imunologia , Humanos , Inflamação , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/imunologiaRESUMO
During the last decade, the worldwide incidence of keratinocyte carcinomas (KC) has increased significantly. They are now the most common malignancy, representing approximately 30% of all cancers. The role of ultraviolet (UV) radiation as a major environmental risk factor for skin cancers is well recognized. The aim of this review is to analyse the current understanding of the nature of beta-human papillomavirus (HPV) and its association with KC and explore the implications for the management and prevention of these cancers. A comprehensive review of the literature on beta-HPV and its association with KC was undertaken, the results reported in the form of a narrative review. A subgroup of HPV that infects the mucosal epithelia of the genital tract has been firmly associated with carcinogenesis. In addition, some HPV types with cutaneous tropism have been proposed to cooperate with UV in the development of KC. The first evidence for this association was reported in 1922 in patients with epidermodysplasia verruciformis (EV). Since then, epidemiological studies have highlighted the higher risk of skin cancer in patients with EV and certain cutaneous HPV types, and in vitro studies have elucidated molecular mechanisms and transforming properties of beta-HPV. Furthermore, in vivo research conducted on transgenic mice models has shown the possible role of beta-HPV in cutaneous carcinogenesis as a co-factor with UV radiation and immunosuppression. There is good evidence supporting the role of beta-HPV in the oncogenesis of KC. The high prevalence of beta-HPV in human skin and the worldwide burden of KC makes the search for an effective vaccine relevant and worthwhile.
Assuntos
Alphapapillomavirus/fisiologia , Betapapillomavirus/fisiologia , Transformação Celular Viral , Suscetibilidade a Doenças , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Neoplasias Cutâneas/etiologia , Transformação Celular Neoplásica , Humanos , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Raios Ultravioleta/efeitos adversosRESUMO
BACKGROUND: Voriconazole and genus beta human papillomavirus (HPV) are independently associated with the development of photo-exposed cutaneous squamous cell carcinoma (SCC) but have not been evaluated concurrently. The objective of this study is to determine the prevalence and type of detectable HPV DNA in voriconazole-associated SCC. METHODS: SCCs from immunosuppressed patients, in those with and without voriconazole exposure, were evaluated by PCR analysis for HPV DNA and compared to SCC from non-immunosuppressed patients. An additional expanded PCR analysis of all SCC that developed in the voriconazole group was also performed. RESULTS: HPV DNA was detected by PCR in all groups regardless of the immunosuppression status (80.5%) with beta HPV most prevalent (64.3-78.6%). However, immunosuppressed patients were significantly more likely to be infected by beta HPV types 5, 8, 14, 20, and 21 (P-value 0.014), and represented the majority of beta HPV types found in the voriconazole group. CONCLUSIONS: In this retrospective study, beta HPV 5, 8, 14, 20, and 21 were commonly detected in voriconazole-associated SCC. The results indicate a possible role of beta HPV in the pathogenesis of cutaneous SCC in photo-exposed areas. Further studies are needed to establish the role of HPV and voriconazole in the pathogenesis of the lesion.
Assuntos
Betapapillomavirus/isolamento & purificação , Carcinoma de Células Escamosas/etiologia , Infecções por Papillomavirus/epidemiologia , Neoplasias Cutâneas/etiologia , Voriconazol/efeitos adversos , Idoso , Betapapillomavirus/genética , DNA Viral/isolamento & purificação , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/prevenção & controle , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase , Estudos RetrospectivosRESUMO
BACKGROUND: Human papillomavirus (HPV) infection is highly prevalent worldwide and may have a role, with sun exposure, in causing cutaneous squamous cell carcinoma. Little is known about the relationship of UV exposure and seroprevalence of cutaneous HPVs in the general population. METHODS: Using multiplex serology, we estimated the seroprevalence of 23 beta and 7 gamma HPVs and 7 other antigens (mu HPV1, HPV63, nu HPV41, alpha HPV16; polyomaviruses HPyV7 and MCV; p53) in a population-based sample of 1,161 Australian 45 and Up Study participants with valid data from blood specimens collected from 2010 to 2012. We calculated prevalence ratios (PR) for the association of each antigen with residential ambient solar UV and other UV-related variables. RESULTS: Seropositivity for at least one beta or gamma HPV was high at 88% (beta HPVs 74%, gamma HPVs 70%), and less in women than men [e.g., PR beta-2 HPV38 = 0.70; 95% confidence interval (CI), 0.56-0.87; any gamma = 0.90; 95% CI, 0.84-0.97]. A high ambient UV level in the 10 years before study enrollment was associated with elevated seroprevalence for genus beta (PRtertile3vs1 any beta = 1.17; 95% CI, 1.07-1.28), and beta-1 to beta-3 species, but not for gamma HPVs. Other UV-related measures had less or no evidence of an association. CONCLUSIONS: Seroprevalence of cutaneous beta HPVs is higher with higher ambient UV exposure in the past 10 years. IMPACT: The observed association between ambient UV in the past 10 years and cutaneous HPVs supports further study of the possible joint role of solar UV and HPV in causing skin cancer.
Assuntos
Betapapillomavirus/isolamento & purificação , Carcinoma Basocelular/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias Cutâneas/epidemiologia , Luz Solar/efeitos adversos , Verrugas/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais/sangue , Antígenos Virais/imunologia , Betapapillomavirus/patogenicidade , Carcinoma Basocelular/etiologia , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales/epidemiologia , Prevalência , Fatores de Risco , Estudos Soroepidemiológicos , Fatores Sexuais , Pele/patologia , Pele/efeitos da radiação , Pele/virologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia , Verrugas/sangue , Verrugas/virologiaRESUMO
We have previously showed that a transgenic (Tg) mouse model with cytokeratin 14 promoter (K14)-driven expression of E6 and E7 from beta-3 HPV49 in the basal layer of the epidermis and of the mucosal epithelia of the digestive tract (K14 HPV49 E6/E7 Tg mice) are highly susceptible to upper digestive tract carcinogenesis upon exposure to 4-nitroquinoline 1-oxide (4NQO). Using whole-exome sequencing, we show that in K14 HPV49 E6/E7 Tg mice, development of 4NQO-induced cancers tightly correlates with the accumulation of somatic mutations in cancer-related genes. The mutational signature in 4NQO-treated mice was similar to the signature observed in humans exposed to tobacco smoking and tobacco chewing. Similar results were obtained with K14 Tg animals expressing mucosal high-risk HPV16 E6 and E7 oncogenes. Thus, beta-3 HPV49 share some functional similarities with HPV16 in Tg animals.
Assuntos
4-Nitroquinolina-1-Óxido/toxicidade , Betapapillomavirus/metabolismo , Neoplasias/genética , Nicotiana/efeitos adversos , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Animais , Betapapillomavirus/genética , Suscetibilidade a Doenças , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Mutação/efeitos dos fármacos , Neoplasias/etiologia , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Infecções por Papillomavirus/genéticaRESUMO
Human papillomaviruses (HPVs) of genus betapapillomavirus (betaHPV) are implicated in skin carcinogenesis, but their exact role in keratinocyte transformation is poorly understood. We show an interaction of HPV5 and HPV8 oncoproteins E6 and E7 with the nuclear mitotic apparatus protein 1 (NuMA). Binding of E6 or E7 to NuMA induces little aneuploidy, cell cycle alterations, or aberrant centrosomes. Intracellular localization of NuMA is not altered by E6 and E7 expression in 2D cultures. However, the localization profile is predominantly cytoplasmic in 3D organotypic skin models. Both viral proteins colocalize with NuMA in interphase cells, while only E7 colocalizes with NuMA in mitotic cells. Intriguingly, a small subset of cells shows E7 at only one spindle pole, whereas NuMA is present at both poles. This dissimilar distribution of E7 at the spindle poles may alter cell differentiation, which may in turn be relevant for betaHPV-induced skin carcinogenesis.
Assuntos
Betapapillomavirus/crescimento & desenvolvimento , Proteínas de Ciclo Celular/metabolismo , Interações Hospedeiro-Patógeno , Queratinócitos/virologia , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/metabolismo , Humanos , Ligação Proteica , Mapeamento de Interação de ProteínasRESUMO
Human papillomaviruses (HPVs) infect the epithelia of skin or mucosa, where they can induce hyperproliferative lesions. More than 220 different HPV types have been characterized and classified into five different genera. Mucosal high-risk HPVs are causative for cancers of the anogenital region and oropharynx. Clinical data from patients with the rare genetic disorder epidermodysplasia verruciformis (EV) indicate that genus beta-HPVs cooperate with ultraviolet (UV) radiation in the development of cutaneous squamous cell carcinoma. In addition, epidemiological and biological findings indicate that beta-HPV types play a role in UV-mediated skin carcinogenesis also in non-EV individuals. However, the mechanisms used by these cutaneous viruses to promote epithelial carcinogenesis differ significantly from those of mucosal HPVs. Recent studies point to a delicate cross-talk of beta-HPVs with the cell-autonomous immunity of the host keratinocytes and the local immune microenvironment that eventually determines the fate of cutaneous HPV infection and the penetrance of disease. This review gives an overview of the critical interactions of genus beta-HPVs with the local immune system that allow the virus to complete its life cycle, to escape from extrinsic immunity, and eventually to cause chronic inflammation contributing to skin carcinogenesis. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.
Assuntos
Betapapillomavirus/fisiologia , Suscetibilidade a Doenças/imunologia , Sistema Imunitário/virologia , Infecções por Papillomavirus/imunologia , Neoplasias Cutâneas/imunologia , Animais , Suscetibilidade a Doenças/virologia , Humanos , Sistema Imunitário/imunologia , Camundongos , Infecções por Papillomavirus/virologia , Neoplasias Cutâneas/virologiaRESUMO
Epidemiological and biological studies provide several lines of evidence for the involvement of cutaneous beta human papillomaviruses (HPVs), together with ultraviolet (UV) radiation, in the development of cutaneous squamous cell carcinoma. These viruses appear to act with a hit-and-run mechanism, being necessary at an early stage of carcinogenesis and being dispensable for the maintenance of the malignant phenotype. Studies in experimental models show that beta HPVs, mainly via the E6 and E7 oncoproteins, are able to promote proliferation and to circumvent cellular stresses induced by UV radiation. These findings support a model of skin carcinogenesis in which beta HPV-infected keratinocytes remain alive despite the accumulation of UV-induced DNA mutations. In this manner, these cells become highly susceptible to progression towards malignancy. Thus, UV radiation is the main driver of skin cancer development, while beta HPVs act as facilitators of the accumulation of UV-induced DNA mutations.