Endocervical cancer is associated with an increase in the ligands and receptors for transforming growth factor-beta and a contrasting decrease in p27(Kip1).
OBJECTIVE
The aim of this study was to investigate the relationship between the expression of the TGF-beta ligands and TGF-beta receptors to the expression of p27(Kip1), a TGF-beta-regulated gene, in endocervical cancer.


METHODS
To examine the expression of TGF-beta and p27(Kip1) 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-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta RI, TGF-beta RII, and p27(Kip1).


RESULTS
Immunostaining for TGF-beta 1, TGF-beta 2, TGF-beta 3, TGF-beta RI, TGF-beta RII, and p27(Kip1) was detected in normal endocervix, with the TGF-betas showing weak cytoplasmic staining, while p27(Kip1) showed strong nuclear staining. Expression of TGF-beta increased significantly upon neoplastic transformation with the TGF-beta ligands and receptors showing strong cytoplasmic staining in adenocarcinoma in situ compared to normal endocervix. Interestingly, expression of TGF-beta was lower in adenocarcinoma than in adenocarcinoma in situ, but still significantly higher than in normal endocervix. TGF-beta 2 and TGF-beta 3 showed higher levels of immunostaining than TGF-beta 1 in adenocarcinomas. In contrast, p27(Kip1) protein expression decreased with progressive malignancy, with lower p27(Kip1) protein levels detected in adenocarcinoma than in adenocarcinoma in situ, while normal endocervix showed the highest level of p27(Kip1) protein expression.


CONCLUSIONS
Elevated expression of the TGF-beta ligands and receptors is found in both cervical adenocarcinoma in situ and adenocarcinoma compared to normal endocervix. In contrast, a progressive decrease in p27(Kip1) 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-beta and p27(Kip1) seen as an elevation of TGF-beta and a reduction of p27(Kip1) expression that may lead to loss of cell cycle control.
Farley
J
J
Department of Obstetrics and Gynecology, Naval Medical Center Portsmouth, Division of Gynecologic Oncology, 150 Kingsley Lane, Norfolk, Virginia 23505, USA.
Gray
K
K
Nycum
L
L
Prentice
M
M
Birrer
M J
MJ
Jakowlew
S B
SB
D030201:Activin Receptors, Type I; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002584:Cervix Uteri / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004801:Eosine Yellowish-(YS); D005260:Female; D016147:Genes, Tumor Suppressor; D006416:Hematoxylin; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009367:Neoplasm Staging; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis*; D013194:Staining and Labeling / Q000379:methods; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
D018797:Cell Cycle Proteins; D008024:Ligands; D008869:Microtubule-Associated Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D004801:Eosine Yellowish-(YS); D006416:Hematoxylin