NUCLEAR PROTOONCOGENE PRODUCTS TRANSACTIVATE THE HUMAN PAPILLOMAVIRUSTYPE-16 PROMOTER

Human papillomavirus (HPV) type 16 and 18 viral genomes are frequently detected in cervical and penile cancer biopsies. Although this strong ly suggests a prominent role for HPV infection in the development of g enital cancer, other genetic or environmental factors are also involve d. Genital cancer is postulated to result from loss of cellular contro l functions, which leads to an unregulated expression of HPV oncogenic proteins. In our study, we determined the trans-activating properties of nuclear proto-oncogene proteins c-Fos, c-Jun and c-Myc on P97 enha ncer/promoter activity of HPV16. Using a CAT-reporter construct contai ning the HPV16 enhancer/promoter element, we investigated the trans-ac tivating effects of c-Fos, c-Jun, c-Myc, and E2 in cervical HT-3 cells . c-Fos and c-Jun overexpression resulted in a 3.3- and 3.1-fold up-re gulation of CAT activity. Only 2-fold induction was determined by co-t ransfection with c-mye and the viral transcription factor E2. Based on these findings, we investigated the expression of HPV DNA (16 and 18) as well as nuclear proto-oncogenes (c-fos, c-jun and c-myc) in nine c ervical cancers by in situ hybridisation. In six out of nine carcinoma s, HPV16 and/or HPV18 DNA was detectable. All tumours showed an intens e and homogeneous expression of c-fos and c-jun mRNA, while the signal for c-mye was detectable only in four specimens. These data suggest t hat deregulation of nuclear proto-oncogene expression may contribute t o an overexpression of HPV-derived oncogenic proteins (E6 and E7), whi ch is generally hypothesised to be an important step in the malignant transformation of HPV-associated tumours.