The human papillomavirus 16 E5 gene potentiates MmuPV1-Dependent pathogenesis

Torres, Alexandra D.; Spurgeon, Megan E.; Bilger, Andrea; Blaine-Sauer, Simon; Uberoi, Aayushi; Buehler, Darya; McGregor, Stephanie M.; Ward-Shaw, Ella; Lambert, Paul F.

doi:10.1016/j.virol.2019.12.002

Cited by 12 publications

(13 citation statements)

References 39 publications

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“…The mouse strain that we used in the present work carries the whole HPV16 early region, which may help to explain why we observed such a high incidence of malignant lesions without using any chemical carcinogen. Besides the major HPV16 E6 and E7 oncogenes, E5 has been suggested to contribute to cell survival and proliferation via multiple pathways including epithelial growth factor receptor activation and stromal remodelling via cyclooxygenase‐2, and to immune evasion via transforming growth factor beta, as previously reviewed . Significantly, HPV16 E5 potentiates the development of lesions induced by MmuPV1 in K14E5 transgenic mice .…”

Section: Discussionmentioning

confidence: 91%

HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice

Mestre

Medeiros‐Fonseca

Estêvão

et al. 2020

The Journal of Pathology

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Head and neck squamous cell carcinomas (HNSCCs) associated with human papillomavirus (HPV) occur specifically in the tonsils and the tongue base, but the reasons for this specificity remain unknown. We studied the distribution of oral and pharyngeal lesions in HPV16-transgenic mice where the expression of all the HPV16 early genes is targeted to keratinising squamous epithelia by the cytokeratin 14 (Krt14) gene promoter. At 30 weeks of age, 100% of mice developed low-and high-grade intraepithelial dysplasia at multiple sites. Twenty per cent of animals developed invasive cancers that remarkably were restricted to the tongue base, in association with the circumvallate papilla. The lesions maintained expression of CK14 (KRT14) and the HPV16 E6 and E7 oncogenes, and displayed deregulated cell proliferation and up-regulation of p16 INK4A . Malignant lesions were poorly differentiated and destroyed the tongue musculature. We hypothesised that the tongue base area might contain a transformation zone similar to those observed in the cervix and anus, explaining why HPV-positive cancers target that area specifically. Immunohistochemistry for two transformation zone markers, CK7 (KRT7) and p63 (TP63), revealed a squamocolumnar junction in the terminal duct of von Ebner's gland, composed of CK7 + luminal cells and p63 + basal cells. Dysplastic and invasive lesions retained diffuse p63 expression but only scattered positivity for CK7. Site-specific HPV-induced carcinogenesis in the tongue base may be explained by the presence of a transformation zone in the circumvallate papilla. This mouse model reproduces key morphological and molecular features of HPV-positive HNSCC, providing a unique in vivo tool for basic and translational research.No conflicts of interest were declared. or HPV18, are associated with HNSCC cases occurring at specific oropharyngeal sitesthe tonsils and the tongue base. This site specificity of HPV-positive lesions suggests the presence of HPV-sensitive transformation zones, such as those described in the uterine cervix and the anus [2,3]. However, those areas, if they indeed exist, Journal of Pathology

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Section: Discussionmentioning

confidence: 91%

HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice

Mestre

Medeiros‐Fonseca

Estêvão

et al. 2020

The Journal of Pathology

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“…We next infected FVB/NJ mice in order to establish a model of papillomavirus-mediated anal infection and disease in immunocompetent mice. FVB/NJ mice have previously been shown to be susceptible to persistent MmuPV1 infection in the skin, penis, cervicovaginal mucosa, and oral tract ( 30 , 33 – 35 , 41 ). Mice were infected using a Greer pick on the dorsal side of the anal tract.…”

Section: Resultsmentioning

confidence: 99%

“…MmuPV1 does not encode an E5 gene. We discovered that the HPV16 E5 gene, as expressed in K14E5 transgenic FVB/NJ mice, enhanced the ability of MmuPV1 to cause pathogenesis of the mouse skin, leading to larger lesions that were less likely to regress and were more likely to progress to SCC than in nontransgenic FVB/NJ mice ( 41 ). E5 also enhanced the ability of MmuPV1 to cause cancers of the female reproductive tract in this study.…”

Section: Discussionmentioning

confidence: 99%

“…In fully immunocompetent C57BL/6J mice, they were unable to detect infection in the anal tract by 6 weeks postinfection, even after partial immunosuppression with CD4 and CD8 antibodies. We sought to investigate whether MmuPV1 could induce high-grade disease and cancer of the anus in immunodeficient mice and whether MmuPV1 is able to persist and induce neoplastic anal disease in the fully immunocompetent FVB/NJ strain, which we have previously found is susceptible to MmuPV1-associated cancers at other sites ( 33 – 35 , 41 ).…”

Section: Introductionmentioning

confidence: 99%

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A Novel Model for Papillomavirus-Mediated Anal Disease and Cancer Using the Mouse Papillomavirus

Blaine-Sauer

Shin

Ward-Shaw

et al. 2021

mBio

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We show, for the first time, that MmuPV1 infection is sufficient to efficiently mediate high-grade squamous intraepithelial lesions in the anal tract of mice using the NSG immunocompromised strain and that MmuPV1, in combination with the chemical carcinogen DMBA, has carcinogenic potential. We further show that MmuPV1 is able to persist for up to 6 months in the anal tract of FVB/NJ mice irradiated with UVB and contributes to high-grade disease and cancer in an immunocompetent strain.

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“…However, the recent discovery of a mouse papillomavirus, MmuPV1, that infects laboratory mice (19)(20)(21) has opened the door to generating infection-based models for papillomavirus-associated pathogenesis in an animal that is highly tractable and can be genetically manipulated. While initially found to cause cutaneous warts in immunodeficient mice, MmuPV1 also causes cutaneous warts in immunocompetent strains with or without alterations to their immune system (19,(22)(23)(24)(25)(26)(27). Importantly, MmuPV1 has a wide tissue tropism: it infects not only cutaneous epithelia but also sites typically implicated in the sexual transmission of HPV, including the mucosa of the female and male genitalia, the anus, and oropharyngeal sites (28)(29)(30)(31)(32)(33)(34).…”

mentioning

confidence: 99%

An Infection-Based Murine Model for Papillomavirus-Associated Head and Neck Cancer

Tao

Buehler

Ward-Shaw

et al. 2020

mBio

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Human papillomavirus (HPV) is the most common sexually transmitted pathogen, and high-risk HPVs contribute to 5% of human cancers, including 25% of head and neck squamous cell carcinomas (HNSCCs). Despite the significant role played by HPVs in HNSCC, there is currently no available in vivo system to model the process from papillomavirus infection to virus-induced HNSCC. In this paper, we describe an infection-based HNSCC model, utilizing a mouse papillomavirus (MmuPV1), which naturally infects laboratory mice. Infections of the tongue epithelium of two immunodeficient strains with MmuPV1 caused high-grade squamous dysplasia with early signs of invasive carcinoma over the course of 4 months. When combined with the oral carcinogen 4-nitroquinoline-1-oxide (4NQO), MmuPV1 caused invasive squamous cell carcinoma (SCC) on the tongue of both immunodeficient and immunocompetent mice. These tumors expressed markers of papillomavirus infection and HPV-associated carcinogenesis. This novel preclinical model provides a valuable new means to study how natural papillomavirus infections contribute to HNSCC. IMPORTANCE The species specificity of papillomavirus has limited the development of an infection-based animal model to study HPV-associated head and neck carcinogenesis. Our study presents a novel in vivo model using the mouse papillomavirus MmuPV1 to study papillomavirus-associated head and neck cancer. In our model, MmuPV1 infects and causes lesions in both immunodeficient and genetically immunocompetent strains of mice. These virally induced lesions carry features associated with both HPV infections and HPV-associated carcinogenesis. Combined with previously identified cancer cofactors, MmuPV1 causes invasive squamous cell carcinomas in mice. This model provides opportunities for basic and translational studies of papillomavirus infection-based head and neck disease.

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The human papillomavirus 16 E5 gene potentiates MmuPV1-Dependent pathogenesis

Cited by 12 publications

References 39 publications

HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice

HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice

A Novel Model for Papillomavirus-Mediated Anal Disease and Cancer Using the Mouse Papillomavirus

An Infection-Based Murine Model for Papillomavirus-Associated Head and Neck Cancer

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