Yamaguchi Munekage, Erdenebaatar Chimeddulam, Saito Fumitaka, Honda Ritsuo, Ohba Takashi, Kyo Satoru, Tashiro Hironori, Katabuchi Hidetaka
Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto-City, Kumamoto, Japan.
Department of Obstetrics and Gynecology, Shimane University of School of Medicine, Izumo, Shimane, Japan.
J Endocr Soc. 2019 Dec 10;4(2):bvz029. doi: 10.1210/jendso/bvz029. eCollection 2020 Feb 1.
To elucidate the mechanism of endometrial cancer (EC) development in young hyperprolactinemic women, this study assessed the hormonal receptor expression, proliferation, and signaling induced by prolactin in endometrial glands (EG) and EC. Prolactin receptor (PRLR) and estrogen receptor alpha (ER-α) in EG were evaluated during the menstrual cycle by immunohistochemistry. The following parameters were compared between EM-E6/E7/TERT cells, which originated from proliferative EG and Ishikawa cells. The expression levels of PRLR, pJAK2 (phosphorylated Janus Activating Kinase 2), its downstream pathways (MAPK, PI3K, and STAT), and ER-α were assessed after adding prolactin by Western blotting. U0126 was used as a MAPK inhibitor. The proliferation caused by estradiol was also examined by MTS assay after adding prolactin. PRLR expression in the EG was significantly higher in the proliferative phase than in the secretory phase, and it was correlated with ER-α expression during the menstrual cycle. After adding prolactin, the expression of pJAK2, PRLR and ER-α was significantly increased in both cell lines, MAPK was activated after adding prolactin in both cell lines, and PI3K and STAT were activated only in EM-E6/E7/TERT cells. The increased proliferation induced by estradiol was enhanced after adding prolactin in both cell lines. All changes caused by prolactin were inhibited in Ishikawa cells pretreated with U0126. Long-term effects of serum prolactin on persistent proliferative endometrium in the presence of estradiol may induce abnormal proliferation of EG in hyperprolactinemic women. Prolactin-PRLR signaling via MAPK may play a crucial role in the progression of EC in hyperprolactinemic women.
为阐明年轻高催乳素血症女性子宫内膜癌（EC）的发病机制，本研究评估了催乳素在子宫内膜腺体（EG）和EC中诱导的激素受体表达、增殖及信号传导。通过免疫组织化学法评估月经周期中EG内的催乳素受体（PRLR）和雌激素受体α（ER-α）。比较了源自增殖期EG的EM-E6/E7/TERT细胞与石川细胞之间的以下参数。添加催乳素后，通过蛋白质印迹法评估PRLR、pJAK2（磷酸化的Janus激活激酶2）及其下游通路（MAPK、PI3K和STAT）以及ER-α的表达水平。U0126用作MAPK抑制剂。添加催乳素后，还通过MTS试验检测了雌二醇引起的增殖情况。EG中PRLR的表达在增殖期显著高于分泌期，且在月经周期中与ER-α表达相关。添加催乳素后，两种细胞系中pJAK2、PRLR和ER-α的表达均显著增加，两种细胞系在添加催乳素后MAPK均被激活，而PI3K和STAT仅在EM-E6/E7/TERT细胞中被激活。添加催乳素后，两种细胞系中雌二醇诱导的增殖增加均增强。用U0126预处理的石川细胞中，催乳素引起的所有变化均受到抑制。在存在雌二醇的情况下，血清催乳素对持续性增殖子宫内膜的长期影响可能会诱导高催乳素血症女性EG的异常增殖。催乳素-PRLR通过MAPK的信号传导可能在高催乳素血症女性EC的进展中起关键作用。
