MEKK4通过JNK/p38上调整合素β3表达促进子宫内膜容受性-现代医学

MEKK4通过JNK/p38上调整合素β3表达促进子宫内膜容受性

单位：南京大学医学院附属鼓楼医院妇产科, 江苏南京 210008

关键词：有丝分裂原活化蛋白激酶激酶激酶4 整合素β3 子宫内膜容受性反复种植失败

分类号：R711.6

出版年·卷·期（页码）：2026·54·第三期（379-385）

摘要：

目的：探究有丝分裂原活化蛋白激酶激酶激酶4(MEKK4)在人子宫内膜和妊娠早期小鼠子宫中的表达及其在子宫内膜容受性中的作用机制。方法：采用免疫组化检测正常生育女性与反复种植失败(RIF)患者子宫内膜组织中MEKK4的表达定位及水平。通过Western blotting检测雌激素(E2)和醋酸甲羟孕酮(MPA)联合处理后Ishikawa细胞中MEKK4的表达变化。进一步在Ishikawa细胞中利用基因沉默和过表达技术，探讨MEKK4及其下游分子c-Jun氨基末端激酶(JNK)/p38信号通路对整合素β3表达的调控作用。最后，通过免疫组化检测妊娠不同天数小鼠子宫中MEKK4的表达模式。结果：MEKK4定位于人子宫内膜上皮细胞而非间质细胞，分泌期子宫内膜MEKK4表达水平显著高于增殖期(P<0.05)。E₂和MPA处理增加Ishikawa细胞中MEKK4的表达，并促进JNK和p38磷酸化。沉默内源性MEKK4表达抑制E₂和MPA对整合素β3和JNK/p38活化的促进作用。过表达MEKK4促进整合素β3表达。最后，在小鼠胚胎着床窗口期的子宫中发现MEKK4表达增加。结论：MEKK4表达于子宫内膜上皮细胞，通过下游分子JNK/p38促进整合素β3表达，在子宫内膜容受性中发挥重要作用。

Objective: To investigate MAP kinase kinase kinase 4(MEKK4) expression in human endometria and in the uteri of mice during early pregnancy and to evaluate the function of MEKK4 in endometrial receptivity.Methods: Immunohistochemistry was used to detect MEKK4 expression and localization in human endometria obtained from normal fertile and recurrent implantation failure(RIF) patients. Western blotting was performed to measure MEKK4 expression in Ishikawa cells upon estrogen(E2) and medroxyprogesteroneacetate(MPA) treatment. The effects of MEKK4 and its downstream factor JNK/p38 on integrin β3 expression were also explored in Ishikawa cells by Western blotting. Finally, we examined the MEKK4 expression pattern in mouse uteri on different days of pregnancy. Results: MEKK4 was located in human endometrial epithelial cells but not in stroma cells, and the level of MEKK4 was significantly higher in human secretory-phase endometria than in the proliferative-phase endometria. MEKK4 expression was upregulated by E2 and MPA treatment in Ishikawa cells, which also stimulated JNK and p38 activation. Silencing endogenous MEKK4 in Ishikawa cells, the positive effects of E2 and MPA on integrin β3 expression and JNK/p38 activation were abolished. Consistently, overexpression of MEKK4 in Ishikawa cells dose-dependently induced integrin β3 expression. Finally, increased MEKK4 expression was detected in mouse uteri during the window of implantation. Conclusion: MEKK4 is expressed in endometrial epithelial cells and promotes integrin β3 expression via downstream JNK/p38 signaling, playing a critical role in endometrial receptivity.

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