Expression of cyclin-dependent kinase inhibitors p16(MTS1), p21(WAF1), andp27(KIP1) in HPV-positive and HPV-negative cervical adenocarcinomas

Inactivation or down-regulation of the cell-cycle inhibitors p16(MTS1), p21 (WAF1), and p27(KIP1) is involved in the carcinogenesis of various human tu mors. In cervical squamous cell carcinomas that are associated with human p apillomavirus (HPV) infection, the expression or function of these proteins is impaired by the action of viral oncoproteins E6 and E7. Comparably less is known about the role of these cyclin-dependent kinase inhibitors in cer vical adenocarcinomas, 15-40% of which are HPV negative. Therefore, we stud ied the expression of p16(MTS1), p21(WAF1), and p27(KIP1) by immunohistoche mistry in 60 cervical adenocarcinomas. HPV infection was determined by PCR, and HPV 16 and 18 E6/E7 oncogene expression was analyzed by RNA-RNA in sit u hybridization. We found significant correlations of strong p16 expression with HPV 16/18 infection and HPV 16/18 E6/E7 oncogene expression (P=0.001) . Moderate or strong p16 expression was also observed in 41% of HPV-negativ e carcinomas, indicating that HPV-independent mechanisms might also lead to p16 overexpression. In addition, stronger p2l and p27 expression was signi ficantly associated with the detection of HPV 16 or 18 E6/E7 transcripts (P =0.015 and 0.030, respectively). Obviously, the tumor suppressor action of these proteins can be overcome in HPV-positive lesions. In contrast, absent or low p16, p21, and p27 immunostaining was observed in most HPV-negative cervical adenocarcinomas and might contribute to carcinogenesis in these tu mors.