Association of p27Kip1, Cyclin E and c-myc expression with progression andprognosis in HPV-positive cervical neoplasms

Recent studies demonstrated that a variety of human cancer cell lines expre ss relatively high levels of p27(Kip1) and that this might be associated wi th increased expression of Cyclin E. There is a feedback inhibitory loop be tween Cyclin E and p27(Kip1), which can be counteracted by elevated c-myc a ctivation. This study analyzed by immunohistochemistry the expression of p2 7(Kip1), Cyclin E and c-myc in a series of HPV-positive cervical tissue sam ples representing various stages of cervical carcinogenesis, using 13 sampl es of normal epithelium, 24 low-grade GIN, 63 high-grade GIN, and 69 sample s of invasive squamous cell carcinoma. To evaluate the cell proliferation, the Ki-67 Labelling Index (LI) was assessed The presence of HPV was investi gated by in situ DNA hybridization. We did nor find any correlation between p27(Kip1) expression and Ki-67 LI in normal and tumor tissue samples. Ther e was evidence for an increase of p27(Kip1) levels from low-grade to high-g rade GIN. Cyclin E, c-myc and the Ki-67 LI were significantly increased dur ing cervical carcinogenesis. Cyclin E and c-myc were positively correlated to cell proliferation in pre-cancerous lesions, but not related to overall survival in invasive carcinomas. Contrary to that, high levels of p27(Kip1) are associated with poor overall survival in invasive cervical carcinomas of clinical stage LB. This may reflect the counteracting function of c-myc in blocking p27(Kip1), thus representing the worst condition of a disturbed tumor cell cycle in cervical carcinoma, ultimately induced by HPV.