Tamoxifen Represses miR-200 MicroRNAs and Promotes Epithelial-to-Mesenchymal Transition by Up-Regulating c-Myc in Endometrial Carcinoma Cell Lines
Tamoxifen Represses miR-200 MicroRNAs and Promotes Epithelial-to-Mesenchymal Transition by Up-Regulating c-Myc in Endometrial Carcinoma Cell Lines
复制标题
Tamoxifen 可抑制 miR-200 microRNA，并通过上调子宫内膜癌细胞系中的 c-Myc 促进上皮细胞向间质细胞的转变。
DOI：
10.1210/en.2012-1607
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发表时间：
2013-02-01
期刊：
影响因子：
4.8
通讯作者：
Yang, An-Gang
中科院分区：
文献类型：
--
作者：
Bai, Jiu-Xu;Yan, Bo;Yang, An-Gang
尽管他莫昔芬（TAM）是一种选择性雌激素受体调节剂，已广泛用于治疗激素反应性乳腺癌，但其雌激素样作用会增加子宫内膜癌的风险。然而，TAM诱导子宫内膜癌的分子机制仍不清楚。在本报告中，我们探讨了 microRNA (miRNA) 在 ECC-1 和 Ishikawa 子宫内膜癌细胞系中 TAM 诱导的上皮间质转化 (EMT) 中的作用，发现 miR-200 通过调节 c-Myc 参与这一过程。当用 TAM 处理时，ECC-1 和 Ishikawa 细胞具有较高的侵袭性和运动性，并进行了 EMT。 miR-200 是一种在多种癌症中具有肿瘤抑制功能的 miRNA 家族，被发现在 TAM 治疗后其含量有所减少。与锌指 E-box 结合同源框 2（被证实为子宫内膜癌细胞系中 miR-200b 的直接靶标）一致，EMT 的其他一些关键因子（如 Snail 和 N-cadherin）增加，而 TAM 处理的细胞中 E-cadherin 减少，导致这些子宫内膜癌细胞中 TAM 诱导 EMT。此外，我们发现c-Myc直接结合并抑制miR-200 miRNA的启动子，并且其在TAM处理的子宫内膜癌细胞中的上调导致miR-200的下调，并最终导致EMT。总的来说，我们的数据表明，TAM 可以抑制 miR-200 家族，并通过上调子宫内膜癌细胞中的 c-Myc 诱导 EMT。这些发现描述了TAM诱导子宫内膜癌EMT的可能机制，并为其提供了潜在的新治疗策略。
Although tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used in the treatment of hormone-responsive breast cancer, its estrogen-like effect increases the risk of endometrial cancer. However, the molecular mechanisms of TAM-induced endometrial carcinoma still remain unclear. In this report, we explored the role of microRNAs (miRNAs) in TAM-induced epithelial-mesenchymal transition (EMT) in ECC-1 and Ishikawa endometrial cancer cell lines and found miR-200 is involved in this process via the regulation of c-Myc. When treated with TAM, ECC-1 and Ishikawa cells were characterized by higher invasiveness and motility and underwent EMT. miR-200, a miRNA family with tumor suppressive functions in a wide range of cancers, was found reduced in response to TAM treatment. Consistent with zinc finger E-box binding homeobox 2, which was confirmed as a direct target of miR-200b in endometrial cancer cell lines, some other key factors of EMT such as Snail and N-cadherin increased, whereas E-cadherin decreased in the TAM-treated cells, contributing to TAM-induced EMT in these endometrial cancer cells. In addition, we showed that c-Myc directly binds to and represses the promoter of miR-200 miRNAs, and its up-regulation in TAM-treated endometrial cancer cells leads to the down-regulation of miR-200 and eventually to EMT. Collectively, our data suggest that TAM can repress the miR-200 family and induce EMT via the up-regulation of c-Myc in endometrial cancer cells. These findings describe a possible mechanism of TAM-induced EMT in endometrial cancer and provide a potential new therapeutic strategy for it.