Activation of G protein coupled estrogen receptor prevents chemotherapy-induced intestinal mucositis by inhibiting the DNA damage in crypt cell in an extracellular signal-regulated kinase 1- and 2- dependent manner.
Activation of G protein coupled estrogen receptor prevents chemotherapy-induced intestinal mucositis by inhibiting the DNA damage in crypt cell in an extracellular signal-regulated kinase 1- and 2- dependent manner.
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G 蛋白偶联雌激素受体的激活通过细胞外信号调节激酶 1 和 2 依赖性方式抑制隐窝细胞中的 DNA 损伤，从而预防化疗引起的肠粘膜炎。
DOI：
10.1038/s41419-021-04325-z
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发表时间：
2021-10-30
影响因子：
9
通讯作者：
Xue B
中科院分区：
文献类型：
--
作者：
Chen G;Zeng H;Li X;Liu J;Li Z;Xu R;Ma Y;Liu C;Xue B
化疗引起的肠粘膜炎（CIM）是化疗的常见不良反应，很少有适当的具体干预措施。我们的目的是确定G蛋白偶联雌激素受体（GPER）在CIM中的作用及其机制。成年雄性C57 BL/6小鼠腹腔注射5-氟尿嘧啶建立CIM模型。选择性GPER激动剂G-1可显着抑制CIM小鼠的体重减轻和组织学损伤，并恢复粘膜屏障功能障碍，包括改善ZO-1的表达、增加杯状细胞数量和降低粘膜渗透性。此外，G-1治疗没有改变5-氟尿嘧啶的抗肿瘤作用。在CIM模型中，G-1治疗降低了前凋亡蛋白和cyclin D1和cyclin B1的表达，逆转了隐窝中TUNEL+细胞、Ki 67+细胞和溴脱氧尿苷+细胞数量的变化。选择性GPER拮抗剂G15可消除G-1对CIM的上述作用，单独应用G15可加重CIM的严重程度。GPER主要在回肠隐窝中表达，G-1可抑制5-FU诱导的回肠隐窝中γ H2 AX+细胞数量的减少和彗星试验结果证实，G-1在体内和体外均能抑制5-FU诱导的回肠隐窝DNA损伤。参考来自GEO数据集的数据，我们验证了GPER激活恢复CIM和5-氟尿嘧啶处理的IEC-6细胞中的ERK 1/2活性。一旦G-1对ERK 1/2活性的影响被ERK 1/2抑制剂PD 0325901消除，G-1对体内和体外DNA损伤的影响也被消除。相应地，PD 0325901抑制G-1对CIM的保护作用的所有表现，如体重和组织学变化、粘膜屏障、隐窝细胞的凋亡和增殖。总之，GPER激活通过ERK 1/2依赖的方式抑制隐窝细胞DNA损伤来预防CIM，这表明GPER可能是预防CIM的靶点。
Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL+ cells, Ki67+ and bromodeoxyuridine+ cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX+ cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.
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