Kadota Yuri, Kato Takeshi, Kasai Kana, Kawakita Takako, Murayama Misaki, Shinya Akari, Sasada Hikari, Katayama Sachiko, Nii Mari, Yamamoto Shota, Noguchi Hiroki, Tamura Kou, Aoki Hidenori, Taniguchi Miyu, Nakagawa Tomotaka, Kaji Takashi, Nishimura Masato, Kinouchi Riyo, Yoshida Kanako, Iwasa Takeshi
Department of Obstetrics and Gynecology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
Endocr J. 2024 Apr 30;71(4):395-401. doi: 10.1507/endocrj.EJ23-0486. Epub 2024 Mar 28.
Activin A promotes the development of endometriotic lesions in a murine model of endometriosis, and the immunohistochemical localization of phosphorylated suppressor of mothers against decapentaplegic homolog 2/3 (pSMAD2/3) complex in endometriotic lesions has been reported. Activin may therefore be involved in the development and proliferation of endometriotic cells via the SMAD signaling pathway. However, few detailed reports exist on SMAD7 expression in endometriosis. The purpose of this study was to investigate the expression of pSMAD2/3 or pSMAD3 and SMAD7 in the orthotopic human endometrium, ovarian endometriosis, and endometriotic lesions in a murine model and the effect of activin A on pSMAD2/3 and SMAD7 expression. We established an endometriosis murine model via the intraperitoneal administration of endometrial tissue and blood from donor mice. Activin A was intraperitoneally administered to the activin group. We immunohistochemically evaluated orthotopic endometria, ovarian endometriotic tissues, and endometriotic lesions in the murine model followed by western blotting. We found that pSMAD3 and SMAD7 were expressed in ovarian endometriosis and orthotopic endometria from patients with and without endometriosis. In the murine model, endometriotic lesions expressed pSMAD2/3 and SMAD7 in the activin and control groups, and higher SMAD7 expression was found in the activin group. To the best of our knowledge, this study is the first to show that SMAD7 expression is upregulated in endometriosis. In conclusion, these results suggest that activin A activates the SMAD signaling pathway and promotes the development of endometriotic lesions, thus identifying SMAD7 as a potential therapeutic target for endometriosis.
激活素A可促进子宫内膜异位症小鼠模型中异位内膜病灶的发展，且已有报道称在异位内膜病灶中存在磷酸化的抗五聚体蛋白母系抑制因子2/3（pSMAD2/3）复合物的免疫组化定位。因此，激活素可能通过SMAD信号通路参与异位内膜细胞的发展和增殖。然而，关于子宫内膜异位症中SMAD7表达的详细报道较少。本研究的目的是调查原位人子宫内膜、卵巢子宫内膜异位症及小鼠模型中的异位内膜病灶中pSMAD2/3或pSMAD3和SMAD7的表达情况，以及激活素A对pSMAD2/3和SMAD7表达的影响。我们通过腹腔注射供体小鼠的子宫内膜组织和血液建立了子宫内膜异位症小鼠模型。激活素A组腹腔注射激活素A。我们对小鼠模型中的原位子宫内膜、卵巢异位内膜组织和异位内膜病灶进行了免疫组化评估，随后进行了蛋白质印迹分析。我们发现，pSMAD3和SMAD7在有或无子宫内膜异位症患者的卵巢子宫内膜异位症和原位子宫内膜中均有表达。在小鼠模型中，激活素组和对照组的异位内膜病灶均表达pSMAD2/3和SMAD7，且激活素组中SMAD7表达更高。据我们所知，本研究首次表明子宫内膜异位症中SMAD7表达上调。总之，这些结果表明激活素A激活SMAD信号通路并促进异位内膜病灶的发展，从而将SMAD7确定为子宫内膜异位症的一个潜在治疗靶点。
