Abstract
Patients suffering from Epidermodysplasia verruciformis (EV), a rare inherited skin disease, display a particular susceptibility to persistent infection with cutaneous genus beta-human papillomavirus (beta-HPV), such as HPV type 8. They have a high risk to develop non-melanoma skin cancer at sun-exposed sites. In various models evidence is emerging that cutaneous HPV E6 proteins disturb epidermal homeostasis and support carcinogenesis, however, the underlying mechanisms are not fully understood as yet. In this study we demonstrate that microRNA-203 (miR-203), a key regulator of epidermal proliferation and differentiation, is strongly down-regulated in HPV8-positive EV-lesions. We provide evidence that CCAAT/enhancer-binding protein α (C/EBPα), a differentiation-regulating transcription factor and suppressor of UV-induced skin carcinogenesis, directly binds the miR-203 gene within its hairpin region and thereby induces miR-203 transcription. Our data further demonstrate that the HPV8 E6 protein significantly suppresses this novel C/EBPα/mir-203-pathway. As a consequence, the miR-203 target ΔNp63α, a proliferation-inducing transcription factor, is up-regulated, while the differentiation factor involucrin is suppressed. HPV8 E6 specifically down-regulates C/EBPα but not C/EBPβ expression at the transcriptional level. As shown in knock-down experiments, C/EBPα is regulated by the acetyltransferase p300, a well-described target of cutaneous E6 proteins. Notably, p300 bound significantly less to the C/EBPα regulatory region in HPV8 E6 expressing keratinocytes than in control cells as demonstrated by chromatin immunoprecipitation. In situ analysis confirmed congruent suprabasal expression patterns of C/EBPα and miR-203 in non-lesional skin of EV-patients. In HPV8-positive EV-lesions both factors are potently down-regulated in vivo further supporting our in vitro data. In conclusion our study has unraveled a novel p300/C/EBPα/mir-203-dependent mechanism, by which the cutaneous HPV8 E6 protein may expand p63-positive cells in the epidermis of EV-patients and disturbs fundamental keratinocyte functions. This may drive HPV-mediated pathogenesis and may potentially also pave the way for skin carcinogenesis in EV-patients.
Highlights
Human papillomaviruses (HPV) are double-stranded non-enveloped DNA viruses that infect epithelial cells of skin or mucosa in a species-specific manner
Patients suffering from the rare genetic disorder Epidermodysplasia verruciformis (EV) are highly susceptible to persistent genus beta-HPV infection and have an increased risk to develop non-melanoma skin cancer at sun-exposed sites
Our data provide evidence for a novel p300/CCAAT/enhancer-binding protein α (C/EBPα)/miR-203dependent pathway, which links HPV8 infection to the expansion of p63-positive cells in the epidermis of EV-patients. This may contribute to the beta-HPV-induced disturbance of epidermal homeostasis and pave the way for skin carcinogenesis
Summary
Human papillomaviruses (HPV) are double-stranded non-enveloped DNA viruses that infect epithelial cells of skin or mucosa in a species-specific manner. They cause hyperproliferative lesions ranging from benign warts to invasive carcinoma. EV-patients display a particular susceptibility to productive and persistent infection with cutaneous genus beta-HPV and they have a high risk to develop non-melanoma skin cancer at sun-exposed sites [3, 4]. The functions of genus beta-HPV oncoproteins are, less well investigated than those of mucosal HPVs. Viral persistence in lesional skin of EVpatients is linked to the ‘virtual absence’ of Langerhans cells, specialized antigen-presenting cells normally residing in the epidermis [5]. The HPV8 E7 protein has been identified as a factor critical for viral immune evasion targeting a key pathway responsible for Langerhans cell attraction in the skin [5]
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