Up-Regulation of α5-Integrin by E-Cadherin Loss in Hypoxia and Its Key Role in the Migration of Extravillous Trophoblast Cells during Early Implantation

被引:51
作者
Arimoto-Ishida, Emi [1 ,2 ]
Sakata, Masahiro [1 ,2 ]
Sawada, Kenjiro [1 ,2 ]
Nakayama, Masahiro [3 ,4 ]
Nishimoto, Fumihito [1 ,2 ]
Mabuchi, Seiji [1 ,2 ]
Takeda, Takashi [1 ,2 ]
Yamamoto, Toshiya [5 ]
Isobe, Aki [1 ,2 ]
Okamoto, Yoko [3 ,4 ]
Lengyel, Ernst [6 ]
Suehara, Noriyuki [3 ,4 ]
Morishige, Ken-ichirou [1 ,2 ]
Kimura, Tadashi [1 ,2 ]
机构
[1] Osaka Univ, Dept Obstet, Grad Sch Med, Suita, Osaka 5650871, Japan
[2] Osaka Univ, Dept Gynecol, Grad Sch Med, Suita, Osaka 5650871, Japan
[3] Osaka Med Ctr, Osaka 5941101, Japan
[4] Res Inst Maternal & Child Hlth, Osaka 5941101, Japan
[5] Sakai Municipal Hosp, Dept Obstet & Gynecol, Osaka 5910064, Japan
[6] Univ Chicago, Dept Obstet & Gynecol, Gynecol Oncol Sect, Chicago, IL 60637 USA
关键词
FOCAL ADHESION KINASE; EPITHELIAL-MESENCHYMAL TRANSITIONS; MATERNAL-FETAL INTERFACE; HUMAN CYTOTROPHOBLASTS; ENDOVASCULAR INVASION; GENETIC INSTABILITY; TUMOR PROGRESSION; CARCINOMA-CELLS; 1ST TRIMESTER; GROWTH-FACTOR;
D O I
10.1210/en.2008-1662
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
During early pregnancy, cytotrophoblast cells differentiate into extravillous trophoblast (EVT) cells and invade the uterine spiral arteries. This physiological process is essential for the development of maternal-fetal circulation. Because EVT cells are exposed to a low-oxygen environment during this process, we investigated the role of hypoxia in the mechanism that regulates the invasive behavior of EVT cells. Real-time PCR and immunofluorescent analysis were performed to investigate how hypoxia influences the expression of E-cadherin in villous explants cultures and in trophoblast-derived BeWo cells. We determined that hypoxia induced E-cadherin down-regulation through Snail up-regulation in villous explant cultures. The influence of E-cadherin loss was examined by analyzing the expression of alpha(5)-integrin and phosphorylated focal adhesion kinase (FAK) by Western blot and evaluating trophoblast invasion using a matrigel invasion assay. E-cadherin loss induced the up-regulation of alpha(5)-integrin, which leads to the tyrosine phosphorylation of FAK, resulting in an increase in the invasive activity of EVT cells. An alpha(5)-integrin neutralizing antibody inhibited the invasion of EVT cells by attenuating FAK tyrosine phosphorylation. Immunohistochemical analysis using clinical placental bed biopsies revealed that alpha(5)-integrin was up-regulated and FAK tyrosine phosphorylated (Try(861)) as EVT cells invade the uterine myometrium, whereas E-cadherin expression was down-regulated. These results suggest that alpha(5)-integrin up-regulation induced by E-cadherin loss under hypoxia has a crucial role in regulating the migration of EVT cells. This finding should help us reach a better understanding of the pathogenesis of critical gestational diseases, such as preeclampsia. (Endocrinology 150: 4306-4315, 2009)
引用
收藏
页码:4306 / 4315
页数:10
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