尽管其患病率和症状的严重性,对子宫腺肌病的发病机制和病因了解甚少。在我们之前的研究中,已经发现scribble定位部分易位到细胞质;然而,其调节机制是已知的。考虑到子宫内膜中超生理雌激素的产生在子宫腺肌病发展中的重要作用,我们分析了雌激素在体内和体外对Scribble定位的影响和机制。首先,我们发现Scribble从基底外侧膜到细胞质的易位在患有子宫腺肌病的女性和小鼠中很容易看到(68%vs27%,分别为60%和10%)。用S-棕榈酰化抑制剂2-溴棕榈酸酯处理48H后,通过免疫荧光观察到Scribble的细胞质富集和palm-Scribble的水平降低,蛋白质印迹,和酰基-生物素交换棕榈酰化测定。高雌激素暴露不仅可以诱导Scribble的部分细胞质易位,而且可以降低palm-Scribble的表达水平。可以通过雌激素受体抑制剂ICI182,780回收。基于以下实验,我们发现,雌激素通过APT通过Scribble蛋白的S-棕榈酰化调节Scribble的定位。最后,进行IHC以验证APT1和APT2在人临床组织标本中的表达,发现它们均急剧增加。此外,APT1或APT2与芳香化酶P450呈正相关。因此,我们的研究可能为子宫腺肌病的发病机制提供新的认识。
Despite its prevalence and the severity of symptoms, little is known about the pathogenesis and etiology of adenomyosis. In our previous study,
Scribble localization has been found to be partially translocated to cytoplasm; however, its regulatory mechanism is known. In consideration of the important role of supraphysiologic estrogen production in the endometrium in the development of adenomyosis, we analyzed the effect and mechanism of estrogen on Scribble localization in vivo and in vitro. Firstly, we found
Scribble translocation from the basolateral membrane to the cytoplasm was easily to be seen in women and mice with adenomyosis (68% vs 27%, 60% vs 10% separately). After treatment with the S-palmitoylation inhibitor 2-bromopalmitate for 48H, cytoplasmic enrichment of Scribble and the reduced level of palm-Scribble was observed by immunofluorescence, Western blot, and acyl-biotin exchange palmitoylation assay. High estrogen exposure could not only induce partially cytoplasmic translocation of
Scribble but also decrease the expression level of palm-Scribble, which can be recovered by estrogen receptor inhibitor ICI182,780. Based on following experiments, we found that estrogen regulated
Scribble localization by APT through S-palmitoylation of
Scribble protein. At last, IHC was performed to verify the expression of APT1 and APT2 in human clinical tissue specimens and found that they were all increased dramatically. Furthermore, positive correlations were found between APT1 or APT2 and aromatase P450. Therefore, our research may provide a new understanding of the pathogenesis of adenomyosis.