基于雌激素代谢调控的白藜芦醇对MNNG诱导子宫内膜癌变的抑制作用

Inhibitory effect of resveratrol on MNNG-induced endometrial carcinogenesis based on estrogen metabolism regulation

目的 考察白藜芦醇(Res)是否可能通过调控雌激素内稳态,进而抑制MNNG诱导小鼠子宫内膜的癌变。方法采用MNNG诱导EC小鼠模型,将小鼠随机分为Control组、Res组、MNNG组、MNNG+Res组。HE染色观察组织病理情况;qPCR检测Ccnd1、CK-19、Erbb2 mRNA的表达;LC-MS/MS检测小鼠血清和子宫中E1、E2、2-MeOE1、4-MeOE1、2-MeOE2、4-MeOE2、16α-OHE1、2-OHE1、4-OHE1、2-OHE2和4-OHE2的含量。结果 MNNG组小鼠子宫内膜腺体增多、拥挤,局灶形成筛孔;MNNG+Res组小鼠子宫内膜腺体减少,趋于正常。与Control组相比,MNNG组Ccnd1、Erbb2 mRNA表达明显升高,MNNG+Res组明显降低。MNNG组小鼠的血清和子宫组织中,2-MeOE2、2-MeOE1和4-MeOE1含量明显下降,4-OHE2含量明显增加,给予Res治疗后,血清中4-MeOE1含量明显升高,子宫组织中2-MeOE2和2-MeOE1含量明显升高,4-OHE2在血清和子宫组织中含量均明显降低。结论 EC小鼠体内雌激素内稳态失衡,Res可以上调雌激素代谢产物2-MeOE2的含量,降低4-OHE2的含量,抑制EC的发生发展。

Aim To observe the changes of estrogens and their metabolites in endometrial cancer mice,and preliminarily explore its potential mechanism of action from the perspective of estrogen homeostasis regulation.Methods EC mouse model was induced by MNNGT.The mice were randomly divided into control group,Res group,MNNG group and MNNG+Res group.HE staining was used to determine tumorigenesis.qPCR was used to detect the mRNA expression levels of Ccnd1,CK-19 ,Erbb2.E1,E2,2-MeOE1,4-MeOE1,2-MeOE2,4-MeOE2,16α-OHE1,2-OHE1,4-OHE1,2-OHE2 and4-OHE2 in serum and uterus of mice were detected by LC-MS/MS.Results The number of endometrial glands in MNNG group significantly increased,while the sulcus could be observed in the foci.MNNG+Res group had mild edema of the myometrium,and the endometrium tended to assume its normal state.The mRNA expressions of Ccnd1 and Erbb2 of MNNG group were significantly higher than those in control group,significantly decreased after combined administration of Res.In MNNG group,the levels of2-MeOE2,2-MeOE1 and4-MeOE1 in serum and uterine tissue samples significantly decreased,while the content of4-OHE2 significantly increased .While after treatment with Res,the content of2-MeOE2 and2-MeOE1 in uterine tissue significantly increased,4-MeOE1 in serum tissue also increased significantly,while4-OHE2 content markedly decreased in serum and uterine tissues.Conclusions For the imbalance of estrogen homeostasis in EC mice,resveratrol can up-regulate the content of estrogen metabolite2-MeOE2,reduce the content of4-OHE2,and inhibit the development of EC.