Dellas A, Schultheiss E, Leivas M R, Moch H, Torhorst J
Department of Obstetrics and Gynecology, University of Basel, Switzerland.
Anticancer Res. 1998 Nov-Dec;18(6A):3991-8.
Recent studies demonstrated that a variety of human cancer cell lines express relatively high levels of p27Kip1 and that this might be associated with increased expression of Cyclin E. There is a feedback inhibitory loop between Cyclin E and p27Kip1, which can be counteracted by elevated c-myc activation. This study analyzed by immunohistochemistry the expression of p27Kip1, Cyclin E and c-myc in a series of HPV-positive cervical tissue samples representing various stages of cervical carcinogenesis, using 13 samples of normal epithelium, 24 low-grade CIN, 63 high-grade CIN, and 69 samples of invasive squamous cell carcinoma. To evaluate the cell proliferation, the Ki-67 Labelling Index (LI) was assessed. The presence of HPV was investigated by in situ DNA hybridization. We did not find any correlation between p27Kip1 expression and Ki-67 LI in normal and tumor tissue samples. There was evidence for an increase of p27Kip1 levels from low-grade to high-grade CIN. Cyclin E, c-myc and the Ki-67 LI were significantly increased during 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 p27Kip1 are associated with poor overall survival in invasive cervical carcinomas of clinical stage IB. This may reflect the counteracting function of c-myc in blocking p27Kip1, thus representing the worst condition of a disturbed tumor cell cycle in cervical carcinoma, ultimately induced by HPV.
近期研究表明，多种人类癌细胞系表达相对高水平的p27Kip1，这可能与细胞周期蛋白E（Cyclin E）表达增加有关。Cyclin E与p27Kip1之间存在反馈抑制环，而c-myc激活水平升高可抵消这种抑制作用。本研究采用免疫组织化学方法，分析了13份正常上皮组织样本、24份低级别宫颈上皮内瘤变（CIN）样本、63份高级别CIN样本以及69份浸润性鳞状细胞癌样本，这些样本代表了宫颈癌发生的各个阶段，检测了p27Kip1、Cyclin E和c-myc在一系列人乳头瘤病毒（HPV）阳性宫颈组织样本中的表达情况。为评估细胞增殖情况，检测了Ki-67标记指数（LI）。通过原位DNA杂交研究HPV的存在情况。我们未在正常组织和肿瘤组织样本中发现p27Kip1表达与Ki-67 LI之间存在任何相关性。有证据表明，从低级别CIN到高级别CIN，p27Kip1水平升高。在宫颈癌发生过程中，Cyclin E、c-myc和Ki-67 LI显著增加。Cyclin E和c-myc在癌前病变中与细胞增殖呈正相关，但与浸润性癌的总生存期无关。与此相反,在临床分期为IB期的浸润性宫颈癌中，高水平的p27Kip1与较差的总生存期相关。这可能反映了c-myc在阻断p27Kip1方面的抵消作用，从而代表了宫颈癌中肿瘤细胞周期紊乱的最严重情况，最终由HPV诱发。
