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Purpose: Persistent human papillomavirus (HPV) infection is associated with the development of certain types of cancer and the dysregulation of microRNAs has been implicated in HPV-associated carcinogenesis. This is the case of microRNA-146a (miR-146a), which is thought to regulate tumor-associated inflammation. We sought to investigate the expression levels of miR-146a during HPV16-mediated carcinogenesis using skin samples from K14-HPV16 transgenic mice which develop the consecutive phases of the carcinogenesis process.Methods: Female transgenic (HPV+/−) and wild-type (HPV−/−) mice were sacrificed at 24–26 weeks-old or 28–30 weeks-old. Chest and ear skin samples from HPV+/− and HPV−/− mice were histologically classified and used for microRNA extraction and quantification by qPCR.Results: Chest skin samples from 24 to 26 weeks-old HPV+/− mice presented diffuse epidermal hyperplasia and only 22.5% showed multifocal dysplasia, while at 28–30 weeks-old all (100.0%) HPV+/− animals showed epidermal dysplasia. All HPV+/− ear skin samples showed carcinoma in situ (CIS). MiR-146a expression levels were higher in HPV+/− compared to HPV−/− mice (p = 0.006). There was also an increase in miR-146a expression in dysplastic skin lesions compared with hyperplasic lesions (p = 0.011). Samples showing CIS had a significant decrease in miR-146a expression when compared to samples showing epidermal hyperplasia (p = 0.018) and epidermal dysplasia (p = 0.009).Conclusions: These results suggest that HPV16 induces the overexpression of miR-146a in the initial stages of carcinogenesis (hyperplasia and dysplasia), whereas decreases its expression at later stages (CIS). Taken together, these data implicate and suggest different roles of miR-146a in HPV-mediated carcinogenesis. [ABSTRACT FROM AUTHOR]

Aims High-risk human papillomavirus (HPV) infection is one of the major causes of infection-related cancers worldwide. MicroRNAs (miRNAs) are a family of non-coding RNAs (ncRNAs), whose dysregulated levels may cause an aberrant expression of genes involved in oncogenic pathways and consequently lead to cancer development. This is the case of the miRNA-150 (miR-150), whose expression in HPV-induced lesions remains unclear and the present work aims to clarify it. We employed K14-HPV16 mice, which express the early genes of HPV16 in basal keratinocytes, leading to the development of hyperplastic and dysplastic skin lesions and squamous cell carcinomas, and are a representative model of HPV-induced cancers. Main methods In order to evaluate the expression of miR-150 in HPV-induced lesions, we performed qPCR in wild-type mice (HPV −/− ) and in skin lesions of K14-HPV16 transgenic mice (HPV +/− ). Matched skin samples were analyzed histologically. Key findings 24–26 weeks-old HPV +/− mice showed diffuse epidermal hyperplasia and focal dysplasia in a hyperplastic background (31.8% incidence), but 28–30 weeks-old HPV +/− mice presented higher incidence of dysplasia (100.0%). MiR-150 was upregulated in HPV +/− mice when compared with HPV −/− mice ( p < 0.001). MiR-150 was also overexpressed in diffuse dysplastic lesions when compared with hyperplastic lesions ( p = 0.005). Significance The present results suggest that miR-150 is overexpressed in HPV-induced lesions in this model and its expression seems to increase with lesion progression, along the process of multi-step carcinogenesis. [ABSTRACT FROM AUTHOR]