Opposite regulation of the HPV 20‐URR and HPV 27‐URR promoters by ultraviolet irradiation and cytokines

Abstract

Epidemiological evidence implicates ultraviolet radiation and genetic changes (e.g., p53 mutations) as important factors in the etiology of nonmelanoma skin cancer. Little is known about a possible role of cutaneous papillomaviruses in these tumors. We previously reported both positive and negative regulation of the promoter activity of a number of HPV types by UV irradiation. To determine the underlying mechanism, we examined the influence of pro-inflammatory cytokines and MAP-kinases induced by UV irradiation by transfecting the HPV 20-URR and the HPV 27-URR into the RKO, HaCaT and H1299 cell lines expressing wild-type or mutated p53 or lacking p53, respectively. IL-1␣, IL-1␤, IL-6, IL-17, TNF-␣, as well as interferon-␣, -␤ and -␥ activated the promoter in the HPV 20-URR but inhibited the HPV 27-URR promoter. The effect of IL-1␣ and UV light was abolished by the addition of IL-1 receptor antagonist. UV irradiation induced a prolonged activation of JNK in HaCaT and H1299 but not in RKO cells, and its dephosphorylation was enhanced in the presence of p53 and the HPV-URRs. © 2001 Wiley-Liss, Inc. Key words: HPV; UV; cytokineEpidemiological evidence has implicated ultraviolet radiation as an important environmental factor in the pathogenesis of nonmelanoma skin cancer (NMSC). 1,2 These tumors occur mainly on sun-exposed sites, and differences in the prevalence of 100-fold for squamous-cell carcinoma and 50-fold for basal-cell carcinoma have been noted among the Caucasian populations of northern Europe and Australia. The incidence rates observed in the white population of Hawaii are, in comparison, substantially lower, possibly suggesting that factors other than changing sun-exposure patterns may play an important role in the etiology of these tumors. 3 Several genetic changes, partially induced by ultraviolet radiation, have been described. These are mutations in the p53 gene, the PTCH gene (chromosome 9q22.3), p21WAF1/CIP1 and p16 NK4/CDKN2A . 4 Papillomavirus (HPV) DNA has been demonstrated in NMSC occurring in renal transplant recipients, as well as in immunocompetent patients. A wide range of HPV types has been demonstrated in biopsies or surface-scrapings of normal skin, 5,6 as well as preand malignant lesions. 2,7 Even though controlled epidemiological studies have to date not been conducted, published data indicate that a few HPV types are more frequently demonstrable than others, independent of which PCR primers had been used for viral DNA amplification. 7,8 The influence of UV irradiation varies on the gene expression of a number of HPV types tested. These HPV types were selected according to their association with different types of skin lesions ranging from benign to malignant. UV irradiation activated the upper regulatory regions (URR) of HPV 1, 5, 7, 20 and 23, whereas it inhibited the URRs of HPV 2, 3, 27, 38 and 77. 4 No activity could be measured for the HPV 41 URR. The presence or absence of wild-type or mutated p53 influenced the gene expression of HPV 20, 27 and 77 but not HPV 41.HPV 20 and HPV ...

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