細胞周期調節因子からみた正常子宮内膜および内膜癌の増殖制御機序(2子宮内膜の機能とその異常)

概要

論文の詳細を見る
The growth of the normal human endometrium is stimulated by estrogen and suppressed by progesterone via the respective receptors, estrogen receptor (ER) and progesterone receptor (PR). This is also the case in some part of endometrial carcinomas. Recent studies have revealed that the cell cycle-related molecules, such as cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors (cdkI) play essential roles in cell proliferation. The present study was undertaken to investigate the possible involvement of the cell cyclerelated molecules in steroid hormone-dependent growth of the normal and neoplastic endometrium. Immunohistochemical staining demonstrated that in the normal endometrial glands, cyclins (D1, E, A, B1) and cdks (cdk4, cdk2, cdc2) were sporadically expressed in the proliferative phase, and the expression of these molecules except for cyclin E and cdk2 was reduced in the secretory phase. The cyclin-and cdk-positive cells were also positive for Ki-67. In endometrial carcinomas, however, overexpression of cyclins and cdks was observed in 30〜75% of the cases examined. Overexpression of cyclin D1, A and cdk4 was more frequently observed in high grade endometrial carcinomas, and survival analysis revealed that cyclin A was an independent prognostic factor. The molecular mechanisms for the estrogen-induced growth of the endometrium was analyzed using cultured glandular cells from normal proliferative endometrium with or without estradiol (E_2) stimulation. Expression of cyclin D1 was detected 4 hours after E_2 treatment, and followed by serial expressions of cyclin E, A, and B1. Immunoprecipitation analysis confirmed the formation of cyclin D1-cdk4 and cyclin E-cdk2 complexes, and subsequent phosphorylation of the Rb protein was also observed. For the intracellular pathway of cyclin D1 up-regulation by estrogen, we hypothesized the involvement of transcription factors, c-Jun/c-Fos, since the cyclin D1 possess c-Jun/c-Fos binding (AP-1) site but lacks the estrogen responsive element. The expression of c-Jun in cultured endometrial cells occurred 2 hours after E_2 stimulation, preceding the cyclin D1 expression. Luciferase assay using various cyclin D1 promoter constructs revealed that the elevated luciferase activity after E_2 stimulation was observed exclusively in the constructs possessing AP-1 site. Increased luciferase activity was also observed when c-Jun expression plasmid was cotransfected with constructs containing AP-1 site. On the other hand, in ER-positive endometrial carcinoma (Ishikawa) cells, the expression pattern of cyclins after E_2 stimulation as well as promoter activity of cyclin D1 differed from those of the normal endometrial cells. Progesterone-induced growth suppression of the normal endometrial glands was examined by immunohistochemical staining of cdkIs (p16, p21, p27). Elevated expression of p27 in the secretory glands and the topological correlation between the p27-positive and the cyclin E/cdk2-positive cells suggests that p27 counteracts to the function of cyclin E/cdk2. Treatment with progesterone in the cultured endometrial cells also induced the expression of p27 protein. Northern blot analysis of p27mRNA and p27 proteindegeneration analysis using cycloheximide showed that elevated expression of p27 protein is due to its prolonged half life rather than transcriptional activation. Transfection of p27 expression plasmid resulted in the decrease of proliferating cell nuclear antigen expression. In conclusion, up-regulation of cyclins and cdks by estrogen may play an essential role in the normal proliferative endometrium, and the estrogen-stimulated expression of cyclin D1 is mediated by c-Jun via AP-1 site. In the secretory endometrium, p27 is an important molecule in progesterone-induced growth suppression. In such ways, the steroid hormone-dependent growth of endometrial glands is regulated by cell cyclerelated molecules. In endometrial carcinomas, however, the expression of these molecules
社団法人日本産科婦人科学会の論文
2000-08-01

細胞周期調節因子からみた正常子宮内膜および内膜癌の増殖制御機序(2子宮内膜の機能とその異常)

スポンサーリンク

概要

著者

関連論文

スポンサーリンク