MicroRNA-34b functions as a potential tumor suppressor in endometrial serous adenocarcinoma
MicroRNA-34b functions as a potential tumor suppressor in endometrial serous adenocarcinoma
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DOI：
10.1002/ijc.27345
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发表时间：
2012-08-15
影响因子：
6.4
通讯作者：
Yaegashi, Nobuo
中科院分区：
文献类型：
--
作者：
Hiroki, Eri;Suzuki, Fumihiko;Yaegashi, Nobuo
子宫内膜浆液性腺癌（ESC）具有侵袭性，预后较差。p53在ESC中经常发生突变。microRNAs （miRNAs）是p53的直接靶点，与癌细胞行为有关。在这项研究中，我们比较了ESC中miRNA的表达水平与子宫内膜样腺癌（EEC）和正常子宫内膜的表达水平。6种mirna被鉴定为ESC特异性的异常下调，其中miR-34b最为明显。发现miR-34b具有启动子超甲基化，当其逆转时，在5-aza-2'脱氧胞苷（DAC）处理的细胞系中恢复miR-34b的表达。miR-34b的异位表达反过来抑制细胞的生长、迁移和最显著的侵袭。我们的研究结果表明p53突变、miR-34b启动子甲基化和肿瘤细胞行为之间存在关系。这些作用可能是由miR-34b的下游靶点介导的，miR-34b是原癌基因间充质上皮转化因子（MET），是子宫内膜癌的已知预后因子。在细胞系中恢复miR-34b后，MET的表达降低。综上所述，我们的数据提示miR-34b在子宫内膜癌的分子发病机制中发挥作用。
Endometrial serous adenocarcinoma (ESC) is aggressive and carries a poor prognosis. p53 is frequently mutated in ESC. microRNAs (miRNAs) are a direct p53 target and have been implicated in cancer cell behavior. In this study, we compared miRNA expression levels in ESC with the levels in endometrial endometrioid adenocarcinoma (EEC) and normal endometria. Six miRNAs were identified as having aberrant down-regulation specific to ESC with miR-34b being most pronounced. miR-34b was found to have promoter hypermethylation, which when reversed, restored miR-34b expression in the cell lines treated with 5-aza-2' deoxycytidine (DAC). Ectopic expression of miR-34b in turn inhibited cell growth, migration and most notably invasion. Our findings suggest a relationship among p53 mutation, miR-34b promoter methylation and tumor cell behavior. These effects are likely mediated by the downstream target of miR-34b, the proto-oncogene mesenchymal-epithelial transition factor (MET), a known prognostic factor in endometrial carcinomas. The expression of MET was reduced following the restoration of miR-34b in cell lines. In summary, our data suggest that miR-34b plays a role in the molecular pathogenesis of endometrial cancer.