Involvement of Hepatocyte Growth Factor-Induced Epithelial-Mesenchymal Transition in Human Adenomyosis
Involvement of Hepatocyte Growth Factor-Induced Epithelial-Mesenchymal Transition in Human Adenomyosis
复制标题
DOI：
10.1095/biolreprod.114.124891
复制
发表时间：
2015-02-01
影响因子：
3.6
通讯作者：
Masuzaki, Hideaki
中科院分区：
文献类型：
--
作者：
Khan, Khaleque Newaz;Kitajima, Michio;Masuzaki, Hideaki
子宫腺肌病通常被认为起源于基底层子宫内膜。肝细胞生长因子（HGF）作为一种雌激素生长因子，在子宫内膜异位症中发挥多种作用，子宫内膜异位症通常被认为是由功能性子宫内膜引起的。在此，我们研究了肝细胞生长因子在子宫腺肌病上皮间质转化（EMT）发生中的作用。从子宫内膜到子宫肌层的全层活检标本收集于子宫切除术后有或无子宫腺肌病的妇女。应用定量RT-PCR和免疫组化技术，从基因和蛋白水平检测了HGF与上皮细胞标志物E-cadherin和间充质细胞标志物N-cadherin的关系。用石川细胞检测了E-cadherin的两个转录抑制因子SLUG和SNAIL的基因和蛋白表达，以及对HGF和雌激素（E-2）的反应。HGF下调E-cadherin和上调N-cadherin mRNA在EECs中的表达，并且观察到弥漫性和局灶性子宫腺肌病妇女的基底肌中HGF和E-cadherin之间的蛋白表达呈负相关。HGF可诱导内皮细胞从鹅卵石样形态转变为梭形细胞，并促进内皮细胞的迁移。石川细胞显示SLUG/SNAIL基因的表达在对HGF和E-2的反应中上调，并且它们之间具有累加效应。用抗HGF抗体或雌激素受体拮抗剂ICI 182720预处理细胞后，HGF和E-2促进的SLUG/SNAIL基因表达显著取消。HGF可能通过诱导子宫内膜-肌层交界处的EMT参与子宫腺肌病患者腺体内陷至子宫肌层深处。
Adenomyosis is commonly believed to arise from the basalis endometrium. As an estromedin growth factor, hepatocyte growth factor (HGF) exhibits multiple functions in endometriosis, a disease commonly believed to arise from the functionalis endometrium. Here, we investigated the role of HGF in the occurrence of epithelial-mesenchymal transition (EMT) in adenomyosis. Full-thickness-biopsy specimens from endometrium to myometrium were collected after hysterectomy from women with and without adenomyosis. The relationship between HGF and E-cadherin (epithelial cell marker) and N-cadherin (mesenchymal cell markers) was examined at the gene and protein levels using endometrial epithelial cells (EECs) in culture and tissues by quantitative RT-PCR and immunohistochemistry. The gene and protein expressions of two transcriptional repressors of E-cadherin, SLUG and SNAIL, were examined using Ishikawa cells and in response to HGF and estrogen (E-2). HGF down-regulated E-cadherin and up-regulated N-cadherin mRNA expression in EECs, and an inverse relationship in protein expression between HGF and E-cadherin was observed in basalis endometria derived from women with diffuse and focal adenomyosis. HGF induced morphological changes of EECs from a cobblestone-like appearance to spindle-shaped cells and promoted migration of EECs. Ishikawa cells exhibited up-regulation of SLUG/SNAIL gene expression in response to both HGF and E-2 with an additive effect between them. HGF- and E-2 promoted SLUG/SNAIL gene expression was significantly abrogated after pretreatment of cells with anti-HGF antibody or ICI 182720, an estrogen receptor antagonist. HGF may be involved in gland invagination deep into the myometrium by inducing EMT at the endo-myometrial junction in women with adenomyosis.