Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells
Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells
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DOI：
10.1210/en.2006-0632
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发表时间：
2006-10-01
期刊：
影响因子：
4.8
通讯作者：
Konishi, Ikuo
中科院分区：
文献类型：
--
作者：
Miyamoto, Tsutomu;Shiozawa, Tanri;Konishi, Ikuo
失配修复受损（MMR）在子宫内膜癌发生的早期阶段至关重要。虽然雌激素暴露被认为是子宫内膜癌的重要危险因素，但雌激素与MMR活性之间的关系仍不确定。本研究旨在阐明雌激素对正常和恶性子宫内膜细胞MMR活性的影响。采用免疫组织化学和免疫荧光技术检测MMR蛋白、hMLH1和hMSH2的表达及其与雌激素的相关性。在培养的正常子宫内膜腺细胞和雌激素受体阳性的子宫内膜癌Ishikawa细胞中，研究雌二醇（E2）对hMLH1/hMSH2蛋白/mRNA表达和体外MMR活性的影响，采用两种异质双工（G/T错配，2碱基插入-缺失环）。正常子宫内膜腺组织中hMLH1和hMSH2的免疫组化表达与血清E2水平呈正相关。E2处理可提高正常子宫内膜腺细胞和石川细胞中hMLH1/hMSH2蛋白和mRNA的表达。E2在两种类型的细胞和异双工细胞中上调MMR活性。免疫荧光分析显示E2增强了两种细胞的增殖和hMLH1/hMSH2的表达；然而，在低E2浓度下，没有hMLH1/hMSH2表达的增殖细胞更常见，这意味着高风险细胞。总的来说，E2诱导的子宫内膜细胞MMR活性上调表明，高雌激素水平是子宫内膜癌发生的内在防御，而绝经后低E2环境下细胞生长和MMR之间的不平衡很容易发生癌变。
Impaired mismatch repair (MMR) is reportedly crucial in the early stages of endometrial carcinogenesis. Although estrogen exposure is considered an important risk factor for endometrial carcinoma, the relationship between estrogen and MMR activity remains undetermined. The present study was undertaken to elucidate the effect of estrogen on MMR activity in normal and malignant endometrial cells. The expression of MMR proteins, hMLH1 and hMSH2, and its correlation with estrogen was examined using immunohistochemical and immunofluorescent techniques. The effect of estradiol (E2) on the expression of hMLH1/hMSH2 protein/mRNA and in vitro MMR activity using two types of heteroduplex (G/T mismatches, 2-base insertion-deletion loops) was examined in cultured normal endometrial glandular cells and estrogen receptor-positive endometrial carcinoma Ishikawa cells. Immunohistochemical expression of hMLH1 and hMSH2 in normal endometrial glands was positively correlated with the serum E2 levels. The expression of hMLH1/hMSH2 protein and mRNA was increased in normal endometrial glandular and Ishikawa cells by E2 treatment. In vitro MMR activity was up-regulated by E2 in both types of cell and heteroduplex. Immunofluorescent analysis demonstrated that E2 enhanced proliferation and hMLH1/hMSH2 expression in both cells; however, proliferating cells without hMLH1/hMSH2 expressions implying high-risk cells were more frequently observed under low E2 concentrations. Collectively, the E2-induced upregulation of MMR activity in endometrial cells suggests that high estrogen levels act as an intrinsic defense against endometrial carcinogenesis, whereas the imbalance between cell growth and MMR under low E2 environment as seen at post-menopause is vulnerable to carcinogenesis.