miR-381 suppresses C/EBPα-dependent Cx43 expression in breast cancer cells.
miR-381 suppresses C/EBPα-dependent Cx43 expression in breast cancer cells.
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DOI：
10.1042/bsr20150167
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发表时间：
2015-10-08
影响因子：
4
通讯作者：
Jiang J
中科院分区：
文献类型：
--
作者：
Ming J;Zhou Y;Du J;Fan S;Pan B;Wang Y;Fan L;Jiang J
miR-381通过直接靶向人乳腺癌细胞中Cx43的新转录因子C/EBPα的3′-UTR抑制Cx43的表达。miR-381-Cx43轴可能是转移性乳腺癌诊断和治疗的一个有用靶点。Cx43（connexin 43）是乳腺癌细胞转移的增强剂。我们先前的研究确定miR-381是Cx43基因表达的间接抑制剂，但其确切机制尚不清楚。在本研究中，使用报告基因分析，我们发现miR-381通过启动子区−500/−250抑制Cx43基因表达。通过定点基因突变，我们证明miR-381可以直接与3′-UTR中的CACUUGUAU序列结合，从而抑制C/EBPα（CCAAT/enhancer-binding protein α）的表达。C/EBPα通过与Cx43基因启动子区-459/-453处的一个典型元件（AATTGTC）结合而被进一步鉴定为一种新的转录因子。在功能上，我们证明了miR-381抑制乳腺癌细胞的C/EBPα和Cx43依赖性迁移和侵袭。最后，我们发现转移性乳腺癌细胞和组织中miR-381水平降低，C/EBPα和Cx43表达增加。因此，我们是第一个确定miR-381抑制乳腺癌细胞中C/EBPα依赖性Cx43表达的人。miR-381-C/EBPα-Cx43轴可能是转移性乳腺癌诊断和治疗的一个有用靶点。
miR-381 suppressed CX43 expression by directly targeting the 3′-UTR of C/EBPα, a novel transcription factor of Cx43 in human breast cancer cells. The miR-381–Cx43 axis might be a useful diagnostic and therapeutic target of metastatic breast cancer. Cx43 (connexin43) is an enhancer of the metastasis of breast cancer cells. Our previous study identified miR-381 as an indirect suppressor of Cx43 gene expression, with the precise mechanism being not understood. In the present study, using a reporter gene assay, we found that miR-381 suppressed Cx43 gene expression via the promoter region −500/−250. With site-directed gene mutation, we demonstrated that miR-381 could directly bind with the sequences CACUUGUAU in the 3′-UTR so as to inhibit C/EBPα (CCAAT/enhancer-binding protein α) expression. C/EBPα was further identified as a novel transcription factor by binding to a canonic element (AATTGTC) locating at −459/−453 in the promoter region of the Cx43 gene. Functionally, we demonstrated that miR-381 suppressed C/EBPα- and Cx43-dependent migration and invasion of breast cancer cells. Finally, we revealed that decreased levels of miR-381 as well as increased expression of C/EBPα and Cx43 in the metastatic breast cancer cells and tissues. Therefore we are the first to identify that miR-381 suppresses C/EBPα-dependent Cx43 expression in breast cancer cells. The miR-381–C/EBPα–Cx43 axis might be a useful diagnostic and therapeutic target of metastatic breast cancer.