Novel Cutaneous Human Papillomaviruses and Biomarkers in the Skin Lesions

Sammanfattning: Non-melanoma skin cancer (NMSC), comprising of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is the most prevalent cancer amongst Caucasians. The main risk factor for the development of NMSC is UV-irradiation but human papillo-mavirus (HPV) might be a co-factor.
We extended the heterogeneity of the genus Betapapillomavirus by characterizing six putative types, HPV93 (species 1), 96 (species 5), 107, 110, 111 and FA75[KI88-03] (species 2). The prevalence of these types in lesions and paired healthy skin were low (< 7%) and the viral loads spanned from 3 copies/cell to less than 1 copy/35,000 cells. Altogether, the four viruses belonging to Betapapillomavirus species 2 were associated with actinic keratosis. In addition, the E7 protein of HPV92, 93 and 96 was able to bind pRb and induce anchorage-independent growth.
Transcriptional activity from the upstream regulatory regions (URR) of HPV8, 38, 92, 93 and 96 was higher in skin- than mucosaderived cells. Transcriptional start sites were mapped at nucleotide position P92 (HPV38), P45 (HPV92), P7439 (HPV93) and P256 (HPV96). Also, responsiveness to UV-B irradiation showed that HPV8 was activated, HPV38 and 93 down-regulated and HPV 92 and 96 were non-responsive. These variable responses among the HPV types within the genus Betapapillomavirus indicate that it is not likely to predict reactivity to UV-B based on genus. In addition, differentiation was shown to up-regulate the transcriptional activity of HPV8, 93 and 96.
Keratoacanthoma (KA) and SCC are histologically difficult to distinguish and thus 19 biomarkers were immunohistochemically investigated in 25 SCC and 64 KA by tissue microarray. The anti-apoptotic Bcl-xL was detected in 84% of the SCC and in 15% of KA, indicating a possible distinguishing marker. HPV DNA was detected in 22% of SCC and 27% of KA and eighty percent of the HPV isolates belonged to the Betapapillomavirus species 2.