Abstract
Cutaneous papillomaviruses are oncogenic viruses that cause severe, persistent infections that can develop into skin cancers within ultraviolet (UV)-exposed skin of immunodeficient individuals, such as those with X-linked severe combined immunodeficiency (XSCID). A canine research model of XSCID exhibits a similar phenotype; these dogs develop severe canine papillomavirus 2 (CPV2) infections that often progress to cancer. Thus, the dog is a natural, spontaneous model to investigate cutaneous papillomavirus infections in immunodeficient patients. The human papillomavirus oncogene E6 contributes to cancer development, in part, by initiating degradation of the tumor suppressor protein p53, or by inhibiting upregulation of p53-dependent genes required within the cell growth arrest and apoptotic pathways, thereby leading to an accumulation of DNA damage required for oncogenesis. Currently, little is known about CPV2, and how it promotes cancer development. The aim of this study was to determine if CPV2 oncogene E6 similarly affects p53 upon activation by UV radiation, as well as the downstream p53-regulated genes necessary to control growth arrest and apoptosis. We determined that cutaneous CPV2 E6 does not degrade p53, or interfere with the upregulation of p53-regulated genes p21, Bax, Bak, or lncRNA-p21, suggesting that CPV2 may use a p53-independent mechanism to contribute to oncogenesis.
Highlights
Papillomaviruses (PV) are host specific, epitheliotropic, circular double-stranded DNA viruses that are widely prevalent among mammals
We examined the response of p53 and p53-regulated genes p21, Bak, Bax, and lncRNA-p21 within UV-exposed normal canine keratinocytes, and with keratinocytes that expressed canine papillomavirus 2 (CPV2) E6
In order to assess the effect of CPV2 E6 on activation of the p53 pathway, we first needed to establish conditions for the induction of DNA damage using UVB in canine keratinocytes to assess p53 responses
Summary
Papillomaviruses (PV) are host specific, epitheliotropic, circular double-stranded DNA viruses that are widely prevalent among mammals. There are over 200 human papillomavirus (HPV) types, which infect mucosal or cutaneous epithelium [1]. Certain high risk (HR) mucosal HPVs are causally associated with anogenital and oropharyngeal cancers. Other HPV types infect skin, and normally cause asymptomatic infections or benign lesions or warts. In immunocompromised individuals, such as those on immunosuppressive therapies due to organ transplantation, those infected with human immunodeficiency virus, or those with genetic immunodeficiencies such as epidermodysplasia verruciformis or X-linked severe combined immunodeficiency (XSCID), some of these cutaneous HPVs have been implicated in the development of severe, persistent cutaneous PV infections that, along with UV radiation, can lead to non-melanoma skin cancers on sun-exposed skin sites [1,2,3,4,5]. In long- term follow-up studies on XSCID patients, for example, approximately 50% of these patients
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