Zhou Yingying, Peng Yangying, Xia Qingqing, Yan Dewen, Zhang Huiping, Zhang Lingmin, Chen Ying, Zhao Xiumin, Li Jie
Department of Laboratory Medicine, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.
Department of Obstetrics and Gynecology, Huangyan Hospital of Wenzhou Medical University, Taizhou First People's Hospital, Taizhou, Zhejiang Province, China.
Reproduction. 2021 Feb;161(2):99-109. doi: 10.1530/REP-20-0172.
Indian hedgehog (Ihh) signaling regulates endometrial receptivity and is an indispensable mediator of embryonic implantation. Hedgehog signaling is known to regulate autophagy, and aberrant regulation of autophagy is critically implicated in the pathogenesis of endometriosis and adenomyosis. However, potential dysregulation of Ihh signaling and its role in autophagy modulation in these diseases remain obscure. In this study, we found that components of Ihh signaling were significantly decreased, whereas the autophagy marker protein, LC3BII, was significantly increased in endometrial tissues of women with endometriosis or adenomyosis. Inhibition of Ihh signaling with the small-molecule inhibitor GANT61 or Gli1 silencing in primary endometrial stromal cells increased autophagic activity, as measured by LC3 turnover assay and tandem mCherry-eGFP-LC3B fluorescence microscopy. Furthermore, we observed that GANT61 treatment significantly attenuated hydrogen peroxide-induced cell death, whereas disruption of autophagy with chloroquine diminished this effect. Collectively, these findings reveal that Ihh signaling is suppressed in endometrial tissues of patients with endometriosis or adenomyosis. This abnormal decrease may contribute to endometrial autophagy activation, which may promote aberrant survival of endometrial cells in ectopic sites in these two gynecological diseases.
印度刺猬因子（Ihh）信号传导调节子宫内膜容受性，是胚胎着床不可或缺的介质。已知刺猬因子信号传导调节自噬，自噬的异常调节与子宫内膜异位症和子宫腺肌病的发病机制密切相关。然而，Ihh信号传导在这些疾病中潜在的失调及其在自噬调节中的作用仍不清楚。在本研究中，我们发现，在子宫内膜异位症或子宫腺肌病患者的子宫内膜组织中，Ihh信号传导成分显著减少，而自噬标记蛋白LC3BII显著增加。用小分子抑制剂GANT61抑制Ihh信号传导或在原代子宫内膜基质细胞中沉默Gli1，通过LC3转换分析和串联mCherry-eGFP-LC3B荧光显微镜检测，增加了自噬活性。此外，我们观察到GANT61处理显著减轻了过氧化氢诱导的细胞死亡，而用氯喹破坏自噬则减弱了这种作用。总的来说，这些发现表明，在子宫内膜异位症或子宫腺肌病患者的子宫内膜组织中，Ihh信号传导受到抑制。这种异常降低可能导致子宫内膜自噬激活，这可能促进这两种妇科疾病异位部位子宫内膜细胞的异常存活。
