MicroRNA-661, a c/EBPalpha target, inhibits metastatic tumor antigen 1 and regulates its functions.
MicroRNA-661, a c/EBPalpha target, inhibits metastatic tumor antigen 1 and regulates its functions.
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DOI：
10.1158/0008-5472.can-09-0898
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Kumar R
中科院分区：
文献类型：
--
作者：
Reddy SD;Pakala SB;Ohshiro K;Rayala SK;Kumar R
MicroRNAs （miRs）已被确定为靶基因调控的转录后修饰因子，并控制在癌症进展中重要的基因产物的表达。在这里，我们发现miR-661通过靶向MTA1 mRNA的3'UTR抑制转移性肿瘤抗原1 （MTA1）的表达，MTA1是人类癌症中广泛上调的基因产物。我们发现内源性miR-661的表达受到c/EBPα转录因子的正调控，而c/EBPα转录因子在癌症进展过程中下调。c/EBPα直接与miR-661染色质相互作用，并结合到含有c/EBPα-共识基序的miR-661推定启动子上。此外，我们发现MTA1蛋白水平逐渐上调，而miR-661及其激活剂c/EBPα水平在由表型范围从非侵入性到高侵入性的MCF-10A细胞系组成的乳腺癌进展模型中下调。c/EBPα在乳腺癌细胞中的表达导致miR-661表达升高，MTA1 3 ' utr -荧光素酶活性和MTA1蛋白水平降低。我们还提供证据表明，miR-661的引入抑制了侵袭性乳腺癌细胞的运动性、侵袭性、非锚定生长和致瘤性。我们相信我们的研究结果首次表明c/EBPα调节miR-661的水平，进而改变人类癌细胞中miR661-MTA1通路的功能。基于这些发现，我们建议进一步研究miR-661在肿瘤细胞中下调MTA1表达的治疗作用。
MicroRNAs (miRs) have been identified as post-transcriptional modifiers of target gene regulation and control the expression of gene products important in cancer progression. Here we show that miR-661 inhibits the expression of metastatic tumor antigen 1 (MTA1), a widely upregulated gene product in human cancer, by targeting the 3’UTR of MTA1 mRNA. We found that endogenous miR-661 expression was positively regulated by the c/EBPα transcription factor, which is downregulated during cancer progression. c/EBPα directly interacted with the miR-661 chromatin and bound to miR-661 putative promoter that contains a c/EBPα-consensus motif. In addition, we found that the level of MTA1 protein was progressively upregulated, while that of miR-661 and its activator, c/EBPα, were downregulated in a breast cancer progression model consisting of MCF-10A cell lines whose phenotypes ranged from non-invasive to highly invasive. c/EBPα expression in breast cancer cells resulted in increased miR-661 expression and reduced MTA1 3’UTR-luciferase activity and MTA1 protein level. We also provide evidence that the introduction of miR-661 inhibited the motility, invasiveness, anchorage-independent growth, and tumorigenicity of invasive breast cancer cells. We believe our findings show for the first time that c/EBPα regulates the level of miR-661 and in turn modifies the functions of the miR661-MTA1 pathway in human cancer cells. Based on these findings, we suggest that miR-661 be further investigated for therapeutic use in down regulating the expression of MTA1 in cancer cells.