Proliferative Action of the Androgen Receptor in Human Uterine Myometrial Cells-A Key Regulator for Myometrium Phenotype Programming
Proliferative Action of the Androgen Receptor in Human Uterine Myometrial Cells-A Key Regulator for Myometrium Phenotype Programming
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DOI：
10.1210/jc.2012-2451
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发表时间：
2013-01-01
影响因子：
5.8
通讯作者：
Dong, Xuesen
中科院分区：
文献类型：
--
作者：
Liu, Liangliang;Li, Yunqing;Dong, Xuesen
背景：在妊娠期间，子宫肌层经历了一个表型编程，从早期的增殖阶段，到中期的合成阶段，再到晚期的收缩阶段，之后细胞开始分娩。目的：研究雄激素受体(AR)在妊娠期子宫肌层细胞中的表达和功能。设计与地点：采用人原代子宫肌层细胞、永生化子宫肌层细胞、大鼠妊娠及输卵管结扎模型。结果：AR在妊娠增生期高表达，合成期开始下降，收缩期达最低水平。生长中胎儿的机械拉伸和孕激素/雌激素比值的降低都是AR蛋白减少的原因。AR独立地调节子宫肌层细胞的增殖配体。AR表达降低延迟了人子宫肌层细胞周期的G1-S相变，并减少了几种细胞周期蛋白的表达。这些AR作用是通过降低IGF-I受体蛋白的稳定性，从而削弱IGF-I下游的PI3K/Akt信号级联来实现的。AR是IGF-I受体蛋白稳定所必需的，通过蛋白酶体和溶酶体途径阻止IGF-I受体泛素化和蛋白质降解。结论：AR是子宫肌层细胞增殖的关键调节因子，提示其在妊娠期间子宫肌层表型规划中起关键作用。(临床内分泌代谢酶98：218-227,2013)
Context: During pregnancy, the myometrium undergoes a phenotype programming starting from an early proliferative stage, to an intermediate synthetic stage, to a late contractile stage, after which the cells commit to labor. Steroid receptors play important roles in regulating myometrial cell phenotype during pregnancy, although detailed mechanisms are not fully defined.Objective: The aim of the study was to investigate the expression and function of the androgen receptor (AR) in myometrial cells during pregnancy.Design and Setting: Human primary myometrial cells, immortalized myometrial cells, rat pregnant and tubal ligation models were used. Immunohistochemistry, Western blot and real-time PCR, cell proliferation, and flow cytometry assays were applied.Results: The AR is highly expressed in the proliferative stage of pregnancy, starts to decrease in the synthetic stage, and reaches the lowest levels in the contractile stage. Both the mechanical stretch by the growing fetus and the decreased ratio of progestin: estrogen are responsible for AR protein reduction. AR regulates myometrial cell proliferation ligand-independently. Decreased AR expression delays the G1-S phase transition of human myometrial cell cycling and reduces expression of several cyclins. These AR actions are mediated through reducing IGF-I receptor protein stability, thus weakening PI3K/Akt signal cascade downstream of IGF-I. AR is required for IGF-I receptor protein stability by preventing the IGF-I receptor from ubiquitylation and protein degradation through both proteosomal and lysosomal pathways.Conclusion: AR is a key regulator for myometrial cell proliferation, suggesting its critical role in myometrium phenotype programming during pregnancy. (J Clin Endocrinol Metab 98: 218-227, 2013)