组蛋白去乙酰化酶3对子宫内膜异位症盆腔纤维化程度及TGF-β1蛋白表达的影响OA
Effect of HDAC3 on pelvic fibrosis and TGF-β1 expression in endometriosis
目的 探讨组蛋白去乙酰化酶3(HDAC3)在子宫内膜异位症(EM)盆腔纤维化及宫腔粘连中的作用及其调控机制.方法 2023年3月至2024年6月于内蒙古医科大学附属医院收集在位内膜及异位内膜组织各30例,分别命名为EM在位组和EM异位组,对照组取材于同期同龄非EM及非激素依赖性的其他卵巢良性肿瘤如卵巢畸胎瘤患者的囊皮标本30例.样本量基于预实验效应量(α=0.05,β=0.20).3组人群的年龄及月经周期阶段差异无统计学意义(均P＜0.05).通过免疫组织化学法检测HDAC3、转化生长因子β1(TGF-β1)的表达,用修订版美国生殖医学学会分期系统(r-AFS)评分评估盆腔粘连.建立EM大鼠模型,并于0～21 d动态观察HDAC3、TGF-β1、α-平滑肌肌动蛋白(α-SMA)蛋白水平的表达,并检测胶原蛋白水平和纤维化面积的变化,采用Pearson分析上述指标的相关性.体外培养人子宫内膜异位上皮细胞系12Z,通过过表达以及抑制HDAC3,检测TGF-β1、胶原蛋白、α-SMA表达的变化,并利用双荧光素酶报告基因实验分析12Z中HDAC3对TGF-β1启动子/报告基因活性的影响.结果 与对照组相比,EM在位组中TGF-β1表达和r-AFS评分显著升高(P＜0.05);与EM在位组相比,EM异位组HDAC3的表达显著上调,TGF-β1 和 r-AFS 进一步升高(P＜0.05).HDAC3 与 r-AFS 呈正相关(r=0.782,P＜0.001),TGF-β1 表达以及痛经(r=0.721)和不孕(r=0.685)均与r-AFS显著正相关(均P＜0.001).在大鼠模型中,HDAC3从0 d开始持续上调至21 d,TGF-β1、胶原蛋白和纤维化面积也随时间递增(均P＜0.05),且大鼠中HDAC3与TGF-β1(r=0.824)、纤维化面积(r=0.802)均呈显著正相关(P＜0.001).细胞实验中,过表达HDAC3促进了 TGF-β1、胶原蛋白和α-SMA的表达(均P＜0.05),而抑制HDAC3则下调了 TGF-β1、胶原蛋白和α-SMA的表达(均P＜0.05).HDAC3过表达组荧光素酶活性升高(P＜0.05),而HDAC3抑制组的荧光素酶活性降低(P＜0.05).结论 HDAC3表达上调与EM盆腔纤维化程度及TGF-β1信号激活呈显著正相关.调控HDAC3显著影响TGF-β1、胶原蛋白及α-SMA的表达水平.
Objective To investigate the role of histone deacetylase 3(HDAC3)in pelvic fibrosis and intrauter-ine adhesions in endometriosis(EM),and to explore its regulatory mechanism.Methods From March 2023 to June 2024,30 eutopic endometrium samples and 30 ectopic endometrium samples were collected from EM patients,designated as EM-eutopic and EM-ectopic groups,respectively.The control group included 30 age-matched women without EM undergoing surgery for non-hormone-dependent benign ovarian tumors.Immunohistochemistry was used to detect HDAC3 and TGF-β1 expression.Pelvic adhesions were evaluated using the revised American Fertility Society(r-AFS)scoring system.An EM rat model was established,and HDAC3,TGF-β1,α-smooth muscle actin(α-SMA),colla-gen expression,and fibrosis area were dynamically observed from day 0 to 21.Pearson correlation analysis assessed rela-tionships among these indicators.In vitro,human endometriotic epithelial 12Z cells were subjected to HDAC3 overexpres-sion or inhibition to detect changes in TGF-β1,collagen,and α-SMA.Dual-luciferase reporter assays were per-formed to evaluate the effect of HDAC3 on TGF-β1 promoter activity.Results Compared with controls,the EM-eu-topic group showed significantly higher TGF-β1 expression and r-AFS scores(P＜0.05).EM-ectopic tissues exhibi-ted further upregulation of HDAC3,with increased TGF-β1 expression and r-AFS scores compared to EM-eutopic tis-sues(P＜0.05).HDAC3 was positively correlated with r-AFS score(r=0.782,P＜0.001),and TGF-β1 expres-sion,dysmenorrhea(r=0.721),and infertility(r=0.685)were significantly associated with r-AFS(all P＜0.001).In rats,HDAC3 expression increased from day 0 to 21,accompanied by elevated TGF-β1,collagen deposition,and fi-brosis area(all P＜0.05).HDAC3 levels were positively correlated with TGF-β1(r=0.824)and fibrosis area(r=0.802)(P＜0.001).In 12Z cells,HDAC3 overexpression increased TGF-β1,collagen,and α-SMA expression(P＜0.05),whereas HDAC3 inhibition decreased their expression(P＜0.05).Luciferase activity was enhanced in the HDAC3 overexpression group and reduced in the HDAC3 inhibition group(P＜0.05).Conclusion Upregulation of HDAC3 is significantly associated with pelvic fibrosis severity and TGF-β1 signaling activation in endometriosis.Modula-ting HDAC3 expression effectively alters TGF-β1,collagen,and α-SMA levels,suggesting HDAC3 as a potential ther-apeutic target for EM-related pelvic fibrosis.
苏冷槾;隋东媛;张新悦;卢建军
内蒙古医科大学附属医院妇产科(内蒙古呼和浩特 010059)内蒙古医科大学附属医院妇产科(内蒙古呼和浩特 010059)内蒙古医科大学附属医院妇产科(内蒙古呼和浩特 010059)内蒙古医科大学附属医院妇产科(内蒙古呼和浩特 010059)
医药卫生
组蛋白去乙酰化酶3子宫内膜异位症盆腔纤维化盆腔粘连
histone deacetylase 3endometriosispelvic fibrosispelvic adhesions
《广东医学》 2026 (1)
14-22,9
中央引导地方科技发展资金项目(2022ZY0186)内蒙古医科大学面上项目(YKD2023MS017)
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