Young Tae Kim and Min Zhao noma. p21WAF1/CIP1 expression usually correlates with favorable prognoses in ovarian, gastric, colorectal, and superficial bladder cancers and in esophageal squamous cell carcinoma. However, in cervical cancer, the conclusions about p21 expression and its prognostic importance vary considerably. Many authors found increased p21 expression in invasive carcinomas33 and an increase in the num- ber of p21-expressing cases during the progres- sion from normal epithelia through precancerous lesions to invasive cervical cancer.29,54 However, others detected an underexpression of p21 in micro-invasive and invasive cervical cancer compared to normal cervical epithelium.55,56 Van de Putte et al.57 did not find any expression of p21 in normal squamous cervical epithelium, in agree- ment with Giannoudis and Herrington58 and Skomedal et al.,33 but in contrast with other reports.29,55 Longer antibody incubation and the use of chronic cervicitis as normal controls may partially account for the differences. However, in- creased expression of p21 in SCC compared to normal epithelium was found in all cases in the abovementioned studies.29,33,55,59 An increase in p21 levels in invasive cancer seems at odds with its function of cell cycle control. However, the p21 level is probably increased in a futile attempt to overcome its impaired or bypassed function. In squamous cell carcinoma, its function could be impaired through the inactivation of p21 by the HPV-16 E7 oncoprotein. Other possibilities in- clude inactivating mutations, mutation of its tar- gets, overexpression of its targets sufficient to titrate p21, or overexpression of proteins in more downstream pathways in cell cycle control.29 On the other hand, Lu et al. reported that ex- pression of p21WAF1/CIP1 was correlated with a favorable prognosis in adenocarcinoma of the uter- ine cervix.60 In most studies, however, there was no significant association of p21 expression and clinicopathological factors or prognosis.29,55,61,62 Al- though the literature on the prognostic signifi- cance of p21 expression in other human cancer types is extensive, no clear picture can be drawn. p27Kip1 p27Kip1 is a negative regulator of the G1 phase of the cell cycle. The p27Kip1 gene is a tumor sup- Yonsei Med J Vol. 46, No. 5, 2005 pressor gene and is frequently lost in tumor cells. It has been implicated in the negative regulation of cell proliferation in response to extracellular signals and is induced upon serum deprivation. In normal epithelial cells, increased expression of p27Kip1 mediates the arrest of cells in the G1 phase of the cell cycle when induced by TGF-β, contact inhibition, or growth in suspension.63 p27 asso- ciates mainly with the cyclin E/CDK2 complex and, through this complex, inhibits pRb phos- phorylation. Overexpression of p27 blocks the cell from entering S-phase.64 Although p27Kip1 is a putative tumor-suppressor gene, mutation or homozygous deletion of this gene is rarely found in human cancer.65 Evidence that p27 may be in- volved in human tumor progression comes largely from studies that have directly measured the expression of p27 protein in clinical tumor samples using immunohistochemical assays. A decrease or absence of p27 protein expression has been shown to be associated with more aggressive clinical behavior in a variety of human tumors, including breast, lung, colon, gastric, and ovarian carcinoma.65 Goff et al. found that p27 was strongly ex- pressed in the normal cervix, in both the epithe- lium and the stroma.66 Other investigators have also found high levels of p27 expression in normal cervix.33,67 Shiozawa et al. revealed that the ex- pression of p27 in the normal squamous epithe- lium of the uterine cervix was observed mainly in the cells of the intermediate and superficial layers, but the expression of p27 was weak in the para- basal cells, which replicate most actively.64 This is consistent with a previous study by Troncone et al.68 In contrary, some studies have indicated that p27 expression is significantly lower in patients with cervical carcinoma compared with normal epithelium and dysplasia.67,68 Huang et al. showed that expression of this protein was absent in 55.3% of the invasive carcinoma tumors.65 The trend of reduced p27 expression in microinvasive and invasive carcinomas further supports the notion that p27 plays a tumor suppressor function during neoplastic transformation in cervical epithelium. Sgambato demonstrated that a decrease in p27 expression is associated with the development of cervical cancer and may play an important role in the early stage of cervical tumorigenesis.69 In fact,