Kai Kentaro, Nasu Kaei, Kawano Yukie, Aoyagi Yoko, Tsukamoto Yoshiyuki, Hijiya Naoki, Abe Wakana, Okamoto Mamiko, Moriyama Masatsugu, Narahara Hisashi
Department of Obstetrics and Gynecology, Oita University, Yufu-shi, Oita, Japan.
Am J Reprod Immunol. 2013 Dec;70(6):485-96. doi: 10.1111/aji.12155. Epub 2013 Sep 13.
The purpose of this study is to evaluate the involvement of death receptor (DR) 6 in the pathogenesis of endometriosis.
Endometriotic cyst stromal cells (ECSCs) and normal endometrial stromal cells (NESCs) were isolated from ovarian endometriotic tissues and the eutopic endometrial tissues, respectively. The effect of valproic acid (VPA) on the DR6 expression in ECSCs was examined. The roles of DR6 in NESC proliferation and apoptosis were investigated with DR6 siRNA transfection. The distribution of DR6 protein in ovarian endometriotic tissues and normal proliferative-phase endometrium was examined by immunohistochemistry. The expression of DR6 mRNA and protein in ECSCs and NESCs was also examined.
Death receptor 6 expression was attenuated in ECSCs and in endometriotic tissues, and its expression was upregulated by VPA stimulation. VPA treatment resulted in an accumulation of acetylated histone H4 in the promoter region of the DR6 gene. DR6 knockdown directed the stimulation of cell proliferation and the resistance to apoptosis in NESCs.
The present findings suggested that DR6 is involved in the pathogenesis of endometriosis by creating the proliferative and anti-apoptotic characteristics of endometriosis. The results also suggest that histone deacetylase inhibitors are promising agents for the treatment of endometriosis.
本研究的目的是评估死亡受体（DR）6在子宫内膜异位症发病机制中的作用。
分别从卵巢子宫内膜异位组织和在位子宫内膜组织中分离出子宫内膜异位囊肿基质细胞（ECSCs）和正常子宫内膜基质细胞（NESCs）。检测丙戊酸（VPA）对ECSCs中DR6表达的影响。通过DR6 siRNA转染研究DR6在NESCs增殖和凋亡中的作用。采用免疫组织化学方法检测DR6蛋白在卵巢子宫内膜异位组织和正常增殖期子宫内膜中的分布。同时检测ECSCs和NESCs中DR6 mRNA和蛋白的表达。
死亡受体6在ECSCs和子宫内膜异位组织中的表达减弱，VPA刺激可使其表达上调。VPA处理导致DR6基因启动子区域乙酰化组蛋白H4积累。敲低DR6可促进NESCs细胞增殖并使其对凋亡产生抗性。
目前的研究结果表明，DR6通过产生子宫内膜异位症的增殖和抗凋亡特性参与了子宫内膜异位症的发病机制。结果还表明，组蛋白去乙酰化酶抑制剂有望成为治疗子宫内膜异位症的药物。
