Endocervical Cancer Is Associated with an Increase in the Ligands and Receptors for Transforming Growth Factor-β and a Contrasting Decrease in p27Kip1

Abstract

Objective. The aim of this study was to investigate the relationship between the expression of the TGF-β ligands and TGF-β receptors to the expression of p27Kip1, a TGF-β-regulated gene, in endocervical cancer.Methods. To examine the expression of TGF-β and p27Kip1 in malignant transformation of the uterine endocervix, a panel of 23 formalin-fixed and paraffin-embedded human cervical specimens, including 8 with benign endocervical glands, 8 with cervical adenocarcinoma in situ, and 7 with cervical adenocarcinomas, was used. Tissues were immunostained with polyclonal antibodies that react specifically with TGF-β1, TGF-β2, TGF-β3, TGF-β RI, TGF-β RII, and p27Kip1.Results. Immunostaining for TGF-β1, TGF-β2, TGF-β3, TGF-β RI, TGF-β RII, and p27Kip1 was detected in normal endocervix, with the TGF-βs showing weak cytoplasmic staining, while p27Kip1 showed strong nuclear staining. Expression of TGF-β increased significantly upon neoplastic transformation with the TGF-β ligands and receptors showing strong cytoplasmic staining in adenocarcinoma in situ compared to normal endocervix. Interestingly, expression of TGF-β was lower in adenocarcinoma than in adenocarcinoma in situ, but still significantly higher than in normal endocervix. TGF-β2 and TGF-β3 showed higher levels of immunostaining than TGF-β1 in adenocarcinomas. In contrast, p27Kip1 protein expression decreased with progressive malignancy, with lower p27Kip1 protein levels detected in adenocarcinoma than in adenocarcinoma in situ, while normal endocervix showed the highest level of p27Kip1 protein expression.Conclusion. Elevated expression of the TGF-β ligands and receptors is found in both cervical adenocarcinoma in situ and adenocarcinoma compared to normal endocervix. In contrast, a progressive decrease in p27Kip1 occurs upon neoplastic transformation of the normal endocervix to cervical adenocarcinoma. These results suggest that neoplastic transformation of the endocervix may be related to dysregulation of TGF-β and p27Kip1 seen as an elevation of TGF-β and a reduction of p27Kip1 expression that may lead to loss of cell cycle control.