Wnt activation downregulates olfactomedin-1 in Fallopian tubal epithelial cells: a microenvironment predisposed to tubal ectopic pregnancy.
Wnt activation downregulates olfactomedin-1 in Fallopian tubal epithelial cells: a microenvironment predisposed to tubal ectopic pregnancy.
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DOI：
10.1038/labinvest.2011.148
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发表时间：
2012-02
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当胚胎未能通过子宫并附着在输卵管的腔上皮上时，就会发生异位妊娠。输卵管异位妊娠是一种常见的妇科急症，95%以上的异位妊娠发生在输卵管壶腹部。在人类，Wnt激活和下调olfm-1(olfm-1)发生在接受性子宫内膜，并与体内胚胎着床相一致。目前尚不清楚在导致EP的输卵管中是否发生了类似的分子变化。我们假设Wnt信号的激活下调了Olfm-1的表达，从而易于诱发EP。我们研究了Olfm-1在非妊娠妇女和EP患者FT中的时空表达，并使用一种新的滋养层球体(胚胎替代物)-输卵管上皮细胞共培养模型(JAR和OE-E6/E7细胞)来研究Olfm-1在球体附着中的作用。非孕期FT壶腹区Olfm-1mRNA表达在卵泡期高于黄体期(p<；0.05)。黄体期EP患者FT中壶腹输卵管Olfm-1的表达低于正常对照组(H-Score=1.3±0.2 vs 2.4±0.5；p<；0.05)。重组Ofm-1(0.2~5μg/ml)处理OE-E6/E7细胞后，球体与OE-E6/E7细胞的黏附受到抑制，而Wnt3a或LiCl3激活Wnt-信号通路，内源性Olfm-1表达减少，球体黏附增加。相反，RNAi抑制Olfm-1的表达增加了球体对OE-E6/E7细胞的黏附。综上所述，Wnt激活抑制了Olfm-1的表达，这可能为人类输卵管内残留胚胎提供了一个有利的微环境，从而导致EP。
Ectopic pregnancy occurs when the embryo failed to transits to the uterus and attached to the luminal epithelium of Fallopian tube. Tubal ectopic pregnancy (EP) is a common gynecological emergency and more than 95% of EP occurs in the ampullary region of the Fallopian tube (FT). In humans, Wnt-activation and down-regulation of Olfactomedin-1 (Olfm-1) occur in the receptive endometrium and coincided with embryo implantation in vivo. Whether similar molecular changes happen in the Fallopian tube leading to EP remains unclear. We hypothesized that activation of Wnt-signaling down-regulates Olfm-1 expression predisposes to EP. We investigated the spatiotemporal expression of Olfm-1 in FT from non-pregnant women and women with EP, and used a novel trophoblastic spheroid (embryo surrogate)-Fallopian tube epithelial cell co-culture model (JAr and OE-E6/E7 cells) to study the role of Olfm-1 on spheroids attachment. Olfm-1 mRNA expression in the ampullary region of non-pregnant FT was higher (p<0.05) in the follicular than theluteal phase. Ampullary tubal Olfm-1 expression was lower in FT from women with EP compared to normal controls at the luteal phase (H-SCORE=1.3±0.2 vs 2.4±0.5; p<0.05). Treatment of OE-E6/E7 with recombinant Olfm-1 (0.2-5 μg/ml) suppressed spheroids attachment to OE-E6/E7 cells; while activation of Wnt-signaling pathway by Wnt3a or LiCl, reduced endogenous Olfm-1 expression and increased spheroids attachment. Conversely, suppression of Olfm-1 expression by RNAi increased spheroids attachment to OE-E6/E7 cells. Taken together, Wnt-activation suppresses Olfm-1 expression and this may predispose a favourable microenvironment of the retained embryo in the Fallopian tube leading to EP in humans.
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