自噬
TFEB
条件基因敲除
生物
细胞生物学
纤维化
癌症研究
信号转导
肌成纤维细胞
间质细胞
转化生长因子
转录因子
转化生长因子β
下调和上调
表型
内科学
细胞凋亡
医学
生物化学
基因
作者
Min Yong,Honggui Zhou,Yuhua Zeng,Yuqin Yao,Hongtao Zhu,Jianguo Hu
标识
DOI:10.1093/molehr/gaae036
摘要
Abstract Abnormal autophagy and the transforming growth factor-β (TGFβ)–SMAD3/7 signaling pathway play an important role in the development of intrauterine adhesions (IUAs); however, the exact underlying mechanisms remain unclear. In this study, we used IUA patient tissue and SMAD7 conditional knockout mice to detect whether SMAD7 effected IUA via regulation of autophagy and the TGFβ–SMAD3 signaling pathway. We applied a combination of techniques for the detection of p-SMAD3, SMAD7, autophagy and fibrosis-related proteins, autophagic flux, and analysis of the SMAD3 binding site. Endometrial tissue of patients with IUA exhibited lower expression levels of SMAD7. In endometrial stromal cells, silencing of SMAD7 inhibited autophagic flux, whereas overexpressed SMAD7 promoted autophagic flux. This SMAD7-mediated autophagic flux regulates the stromal–myofibroblast transition, and these phenotypes were regulated by the TGFβ–SMAD3 signaling pathway. SMAD3 directly binds to the 3ʹ-untranslated region of transcription factor EB (TFEB) and inhibits its transcription. SMAD7 promoted autophagic flux by inhibiting SMAD3, thereby promoting the expression of TFEB. In SMAD7 conditional knockout mice, the endometria showed a fibrotic phenotype. Simultaneously, autophagic flux was inhibited. On administering the autophagy activator rapamycin, this endometrial fibrosis phenotype was partially reversed. The loss of SMAD7 promotes endometrial fibrosis by inhibiting autophagic flux via the TGFβ–SMAD3 pathway. Therefore, this study reveals a potential therapeutic target for IUA.
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