Abstract
A growing proportion of oropharyngeal squamous cell carcinomas (OPSCC) are associated with infection by high-risk human papillomavirus (HPV). For reasons that remain largely unknown, HPV+OPSCC is significantly more common in men than in women. This study aims to determine the incidence of OPSCC in male and female HPV16-transgenic mice and to explore the role of female sex hormone receptors in the sexual predisposition for HPV+ OPSCC. The tongues of 30-weeks-old HPV16-transgenic male (n = 80) and female (n = 90) and matched wild-type male (n = 10) and female (n = 10) FVB/n mice were screened histologically for intraepithelial and invasive lesions in 2017 at the Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Portugal. Expression of estrogen receptors alpha (ERα) and beta (ERβ), progesterone receptors (PR) and matrix metalloproteinase 2 (MMP2) was studied immunohistochemically. Collagen remodeling was studied using picrosirius red. Female mice showed robust ERα and ERβ expression in intraepithelial and invasive lesions, which was accompanied by strong MMP2 expression and marked collagen remodeling. Male mice showed minimal ERα, ERβ and MMP2 expression and unaltered collagen patterns. These results confirm the association of HPV16 with tongue base cancer in both sexes. The higher cancer incidence in female versus male mice contrasts with data from OPSCC patients and is associated with enhanced ER expression via MMP2 upregulation.
Highlights
Infection with high-risk human papillomavirus (HPV) is associated with a number of epithelial cancers, most prominently cervical cancer and other anogenital cancers and a growing subset of head and neck squamous cell carcinomas, many of those located in the oropharynx (OPSCC) [1]
The incidence of SCC was slightly higher in HPV16-transgenic female compared with male mice: six female mice showed low-grade dysplasia, two showed high-grade dysplasia, and two showed SCC; in the male group, six mice showed low-grade dysplasia, two showed high-grade dysplasia, and a single animal was diagnosed with SCC
We compared the mRNA expression of the HPV16 E6, E7 and E5 oncogenes in male and female K14-HPV16 tongue tissue samples
Summary
Infection with high-risk human papillomavirus (HPV) is associated with a number of epithelial cancers, most prominently cervical cancer and other anogenital cancers and a growing subset of head and neck squamous cell carcinomas, many of those located in the oropharynx (OPSCC) [1]. Using mice where the entire early HPV16 genomic region is expressed under the control of the cytokeratin 14 (Krt14) gene promoter, we demonstrated that HPV is sufficient to induce intraepithelial lesions in multiple oral and oropharyngeal sites, but that invasive lesions are restricted to the tongue base This was associated with the presence of a squamocolumnar junction located in the circumvallate papilla, similar to the anal squamocolumnar junction, which constitutes a transformation zone comprising cells that are uniquely sensitive to HPV-induced transformation [10]. Upon exposure to a chemical carcinogen, squamous cell carcinomas arise at multiple locations, presumably arising from HPV-induced intraepithelial lesions [11] These studies were conducted in female mice, but male patients are consistently more affected by HPV+OPSCC than women [2]. We hypothesized that sex-related differences in OPSCC incidence are associated with different expression levels of female sex hormone receptors, and the present work aims to compare the incidence and distribution of intraepithelial and invasive lesions in male and female HPV16-transgenic mice and to investigate the possible role of sex hormone receptors in determining cancer incidence in both sexes
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