Cell Cycle and Cervical Carcinoma in that study, p27 expression was already reduced in preinvasive lesions of the cervix and became progressively more evident during the progres- sion from low- to high-grade SIL and from SIL to carcinoma. This result of p27 expression in cer- vical carcinomas is in agreement with similar findings in several other types of human malig- nancies63 and with previous reports of cervical cancers.64,65,68 The lower levels of p27 in invasive cervical carcinomas compared with normal epithelium might be explained simply as a direct conse- quence of the increased cell proliferation, re- flecting the fact that the time spent by the neo- plastic population in the early part of the cell cycle is reduced.68 Shiozawa et al. demonstrated that p27 seemed to be involved in the regulation of growth and differentiation in the normal squa- mous epithelia of the uterine cervix.64 Thus, the apparently normal function of p27 may be pre- served in preinvasive CIN lesions. However, invasive SCC samples showed a paradoxic over- expression of p27, which may represent aberrant regulation and/or function of the p27 protein. Most studies indicate that low levels of p27 are not found to be predictive for reduced survival and do not correlate with age, menopausal status, tumor stage, grade of differentiation, histological type, or HPV infection.33,62,65,67 However, Huang et al. demonstrated that loss of p27 expression was significantly associated with lymph node metas- tasis.65 Contrary to that, in a study by Dellas et al., high levels of p27 were associated with poor survival in invasive cervical carcinomas of clinical stage IB.70 In summary, p27Kip1 expression is often shown to be detectable only in a small percentage of cervical cancers33,67 and to be lower in cervical carcinoma compared with normal epithelium and precancerous lesions.62,64,65,68 No relationship was observed between expression of p27Kip1 and proliferative activity in cervical cancer as well as in other cancers, suggesting that deregulated ex- pression of p27Kip1 might contribute to tumor formation through mechanisms other than in- creased cell proliferation.64,68 Cyclin E Cyclin E exists in two isoforms with high homology, designated cyclin E1 and E2. No major differences in expression or function between cy- clin E1 and E2 have been found, and their ex- pression has been assumed to be governed by the same molecular circuitry.71,72 Cyclin E, whose catalytic partner is CDK2, is another rate-limiting regulator of the G1 phase of the cell cycle,73 and increased expression of cyclin E has been found in several types of tumors. Appropriate regulation of this cyclin is essential for S-phase transition and numerous processes that determine the accuracy of chromosome replication. It can play a role simi- lar to that of cyclin D1, driving the cell cycle by phosphorylation of Rb, p107, and p130 and the subsequent release of E2F and transcription of key proteins. Cyclin E appears in late G1 after passage through the restriction point. The level of cyclin E peaks in late G1 and disappears again in early S phase. Even though gene amplification and post-tran- scriptional modification are the common causes of aberrant cyclin E expression in different malig- nancies, high-risk-HPV oncoprotein-associated mechanisms might contribute to the aberrant cyclin E expression in cervical lesions. Untethering of E2F factors by the action of the HPV E7 protein could result in the overexpression of cyclin E. This connection, however, is not enough to explain the highly expressed cyclin E in cervical epithelium. The HPV oncoprotein E7 was demonstrated in complexes with cyclin E and cyclin A, thus elimi- nating phase-dependent variation in activity. Also, the HPV E7 was found to interact with p21 and thereby block p21-mediated inhibition of cyclin E-associated kinase activity.5,75 In normal cervical squamous epithelium, cyclin E expression was not immunohistochemically de- tectable or was very weak.28,64,67,74,76 However, cyclin E expression was increased in both low- and high-risk HPV-infected squamous and glan- dular lesions.28,70 Cyclin E expression correlated strongly with morphologic features of the HPV-in- fected lesions, and has been observed in inter- mediate, and partly in superficial, cells from LSIL and HSIL, implying sequential dysregulation.77 A positive correlation between cyclin E expression and cell proliferation rate in precancerous lesions was demonstrated by some studies.70,78 In con- trast, Kanai et al. showed lower proliferation rates Yonsei Med J Vol. 46, No. 5, 2005